Intracellular metal ion-based chemistry for programmed cell death

Abstract

Intracellular metal ions play essential roles in multiple physiological processes, including catalytic action, diverse cellular processes, intracellular signaling, and electron transfer. It is crucial to maintain intracellular metal ion homeostasis which is achieved by the subtle balance of storage and release of metal ions intracellularly along with the influx and efflux of metal ions at the interface of the cell membrane. Dysregulation of intracellular metal ions has been identified as a key mechanism in triggering programmed cell death (PCD). Despite the importance of metal ions in initiating PCD, the molecular mechanisms of intracellular metal ions within these processes are infrequently discussed. An in-depth understanding and review of the role of metal ions in triggering PCD may better uncover novel tools for cancer diagnosis and therapy. Specifically, the essential roles of calcium (Ca²⁺), iron (Fe^2+/3+), copper (Cu^+/2+), and zinc (Zn²⁺) ions in triggering PCD are primarily explored in this review, and other ions like manganese (Mn^2+/3+/4+), cobalt (Co^2+/3+) and magnesium ions (Mg²⁺) are briefly discussed. Further, this review elaborates on the underlying chemical mechanisms and summarizes these metal ions triggering PCD in cancer therapy. This review bridges chemistry, immunology, and biology to foster the rational regulation of metal ions to induce PCD for cancer therapy.

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Yawen You

Yawen You is a postdoctoral fellow in Professor Hu's laboratory at the School of Pharmacy, University of Wisconsin-Madison. She received her PhD degree at the University of Science and Technology of China. Her research focuses on inorganic catalysis, drug delivery, and cell therapy.

Quanyin Hu

Quanyin Hu is an Assistant Professor at School of Pharmacy, University of Wisconsin-Madison (UW-Madison). He received his PhD degree in Biomedical Engineering at University of North Carolina at Chapel Hill (UNC-CH) and North Carolina State University. Before he joined UW-Madison, he was a postdoc associate at Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology (MIT). His research group focuses on drug delivery, cell therapy, immunotherapy and personalized therapy.

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1. Introduction

As one of the most common heterogeneous diseases, cancer has been characterized as a cell death disorder. Cell death plays a significant role in the homeostasis of multicellular organisms. According to the type of triggered stimulus, cellular context, and morphological criteria, cell death is categorized into accidental cell death (ACD) and programmed cell death (PCD).¹ ACD is an out-of-control biological process. However, PCD relies on elaborate regulations that can be modulated by genetic, pharmacological, and biochemical interventions.^2,3 Current PCD has been critically summarized into molecularly oriented definitions by the Nomenclature Committee on Cell Death (NCCD), including necroptosis, pyroptosis, ferroptosis, cuproptosis,⁴ entotic cell death, netotic cell death (NETosis), parthanatos, lysosome-dependent cell death, autophagy-dependent cell death, alkaliptosis, and oxeiptosis (Fig. 1). The molecular mechanisms responsible for triggering and transmitting distinct PCD are intricately interconnected. Therefore, different lethal subroutines within PCD can significantly impact cancer progression and treatment outcomes. In the early stages of oncogenesis, cancer cells may resist cancer treatments due to mutations disrupting the PCD pathway, thereby underscoring the evasion of PCD as a hallmark of cancer. The strategic initiation and management of PCD signals, either individually or synergistically, presents a means to surmount such resistance in specific cancer subtypes.^5,6 Collectively, there is an urgent need to clarify the deep pathogenesis of cancer diseases combining various mechanisms of PCD for combating cancers.

Fig. 1 Timeline of the discovery of multiple forms of PCD.

Recently, knowledge of the mechanisms underlying PCD has increased substantially, with multiple PCD-inducing targets being identified and exploited as new therapeutic modalities. Dyshomeostasis of intracellular metal ions, i.e., a deficiency or excess, can alter intracellular signaling thereby contributing to diverse PCDs. For example, Fe^2+/3+, Cu^+/2+, Mn^2+/3+/4+, and Co^2+/3+ can disrupt redox homeostasis to produce excessive reactive oxygen species (ROS) and further induce cancer cell death by apoptosis, ferroptosis, or other PCDs.^7–10 Furthermore, excess Cu⁺ can destabilize iron–sulfur (Fe–S) proteins, resulting in cuproptosis.¹¹ Ca²⁺, Zn²⁺, and Mg²⁺ play vital roles in enzyme catalysis and cellular metabolism.^12,13 Particularly, Zn²⁺ and Mg²⁺ can induce apoptosis through the starvation effect by inhibiting the activity of glycolysis-related enzymes.¹⁴ In addition, Ca²⁺ can trigger the release of different caspases to induce apoptosis and pyroptosis.¹⁵ Therefore, it is promising to design metal ion-based chemistry to either disrupt or maintain intracellular metal ions homeostasis to alter cell fate with the goal of boosting or suppressing PCD.

To leverage the vital role of metal ions in PCD for cancer treatment, in this review, we will elaborate on the signaling pathways of each type of PCD with a particular focus on the contribution of intracellular metal ions. This review will first describe the importance of intracellular metal ions in living systems. Next, the impacts of dyshomeostasis of intracellular metal ions will be outlined. Then, we will introduce the latest research progress in different types of PCD (Fig. 2). Further, we will introduce metal ion-induced chemical reactions and illustrate how they can help regulate cancer cell death mechanisms. To that end, we will discuss the rational development and prospects of precision anti-tumor therapeutic strategies through regulating intracellular metal ions for PCD.

Fig. 2 A schematic illustration of metal ion-triggered programmed cell death (PCD) for cancer cells.

2. Intracellular metal ion-related chemistry reaction

Metal ions, through catalyzing or initiating various chemical reactions, contribute to the production of diverse chemicals, species, and products crucial for sustaining normal biological functions.^16,17 Specifically, numerous metal ions assume pivotal roles, influencing enzyme catalytic reactions, inflammatory responses, oxidative stress and cellular physiological behaviors.¹⁸ Notably, calcium (Ca²⁺), iron (Fe^2+/3+), copper (Cu^+/2+), and zinc (Zn²⁺) ions, among others, are indispensable for the complexities of tumorigenesis, impacting both developmental processes and the sensitivity or resistance of tumors to treatment.^19,20 This underscores the increasing significance of metal ions in cancer biology and therapy.

2.1 Calcium

2.1.1 Homeostasis of calcium. Calcium emerges as a pivotal micronutrient and secondary messenger crucially implicated in orchestrating cellular and physiological responses to a myriad of stimuli (Fig. 3).^21,22 Its biological functions exhibit remarkable versatility, governing processes integral to birth, life, and death.²³ The distribution of Ca²⁺ spans distinct cellular locales and concentrations, with endoplasmic reticulum (ER) [Ca²⁺] between 250 and 600 mM, and mitochondrial and nuclear-free [Ca²⁺] at about 100 nM.²⁴ The maintenance of intracellular [Ca²⁺] ([Ca²⁺]i) homeostasis is paramount for the regulation of diverse biological processes through intricate chemical reactions. [Ca²⁺]i modulation is orchestrated by an array of mechanisms, including receptor-operated, store-operated, and voltage-sensitive ion channels, ion exchangers, Ca²⁺-binding proteins, as well as mitochondrial, ER, and sarcoplasmic reticulum (SR) Ca²⁺.^25,26

Fig. 3 Schematic illustration of intracellular calcium ion-related chemistry reaction.

2.1.2 Enzyme activation. Ca²⁺ predominantly engages with oxygen donors, displaying a coordination number typically falling within the range of five to eight, with seven being the most prevalent.²⁷ The binding constants ascribed to Ca²⁺ interactions span a spectrum from weak to strong affinities. This diversity in binding characteristics is attributed to the myriad proteins with which calcium engages. Among these functions are the initiation of crucial stereochemical modifications in active sites, the facilitation of protein dimerization, the establishment of a significant electrostatic potential promoting protein association with anionic membrane leaflets, and the compensation for negatively charged protein loops. Ultimately, negatively charged aromatic amino acids easily penetrate the cell membrane bilayer, concomitant with other essential functions.

Intracellular Ca²⁺ release channels,²⁸ exemplified by the ryanodine receptor (RyR) and inositol 1,4,5-triphosphate receptor (IP₃R) channels, play pivotal roles in cellular signaling.²⁶ Activation of RyR channels is triggered by heightened [Ca²⁺]i or through protein signaling events. In a canonical signal transduction cascade, a G protein-coupled receptor (GPCR) stimulates the generation of IP₃, subsequently activating IP₃R channels through IP₃ binding, thereby facilitating Ca²⁺ release from the ER and SR.²⁹ The ER lumen serves as the principal reservoir for intracellular calcium; its depletion instigates calcium accumulation in the mitochondrial matrix, NADPH oxidase complex assembly, and ROS production, culminating in the initiation of NETosis.³⁰ Calcium-dependent interactions with key molecular chaperones and enzymes within the ER, including binding immunoglobulin protein (BiP), calreticulin (CRT), and transmembrane and coiled-coil domains 1 (TMCO1), are crucial for maintaining calcium homeostasis and enzymatic activities.^31–34 Moreover, when cytosolic calcium overload, oxidative stress, ER stress, or other cellular stimuli occur, they can activate pro-apoptotic and ferroptotic proteins that induce apoptosis and ferroptosis.^35,36

2.1.3 Signal transduction.
2.1.3.1 Oxidative phosphorylation. [Ca²⁺]i is meticulously regulated both temporally and spatially, playing a crucial role in signal transduction pathways. Mitochondria, integral to this regulation, actively buffer [Ca²⁺]i levels through the dynamic uptake and release of Ca²⁺, concurrently facilitating ATP production by the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS).³⁷ Precise modulation of OXPHOS activity by appropriate Ca²⁺ levels in the mitochondrial matrix is indispensable for maintaining the optimal rate of ATP production. In physiological states, the accumulation of Ca²⁺ within mitochondria enhances oxidative metabolism by modulating Ca²⁺-sensitive dehydrogenases and metabolite carriers.³⁸ However, mitochondrial Ca²⁺ overload leads to excessive ROS generation, diminished ATP production, and mitochondrial outer membrane permeabilization (MOMP). This phenomenon may culminate in cell death facilitated by the release of pro-apoptotic factors including cytochrome C (cytoC) and activated caspases.³⁹

The Ca²⁺-permeable channel transient receptor potential melastatin 2 (TRPM2) establishes a unique linkage between the intracellular redox status and the adenine nucleotide metabolic network.⁴⁰ Thus, TRPM2 emerges as a critical regulator by influencing ROS production and the antioxidant response. This modulation is achieved by facilitating Ca²⁺ entry via channel activation, ultimately influencing cell survival and the progression of tumors in various cancers.

2.1.3.2 Inflammatory reactions. In the pathogenesis of cardiovascular and related diseases, inflammation assumes a contributory role. Specifically, Ca²⁺-calmodulin-dependent protein kinase II (CaMKII) mediates inflammation within the myocardial microenvironment, precipitating cellular dysfunction, heightened inflammatory responses, and cellular demise. The overactivation of CaMKII disrupts normal myocardial functioning by engaging various inflammatory pathways. Furthermore, CaMKII exerts influence over mitochondrial Ca²⁺ homeostasis, with its hyperactivation fostering the opening of the mitochondrial permeability transition pore (mPTP).⁴¹ Activation of the NOD-like receptor (NLR) protein 3 (NLRP3) inflammasome constitutes a crucial mechanism that connects the functionality and integrity of mitochondria to innate immunity.⁴² Following cardiomyocyte damage, an inflammatory cascade is triggered by the generation of cytokines, damage-associated molecular patterns (DAMPs), and extracellular vesicles.⁴³ This inflammatory process is underpinned by the release of DAMPs, crucial for orchestrating immunogenic cell death (ICD), with constituents such as the ER chaperone calreticulin and ATP.⁴⁴ The release of DAMPs relies on a danger signaling module induced by select anticancer treatments that are characterized by oxidative-ER stress.

2.2 Iron

2.2.1 Homeostasis of iron. Ferritin predominantly serves as the reservoir for iron, which is further integrated into heme and Fe–S cluster proteins within mammalian cells.⁴⁵ Its distribution spans distinct cellular locales, with concentrations approximating 16 μM in mitochondria, 6 μM in the cytosol, 7 μM in nuclei, and 16 μM in lysosomes.⁴⁶ Iron emerges as a redox-active metal, acting as a prosthetic group in enzymes pivotal to cellular biological processes (Fig. 4).⁴⁷ As a common cofactor in redox reactions, Fe²⁺ is unstable. It catalyzes the generation of ROS via the Fenton reaction. Although Fe²⁺ constitutes a cytosolic labile iron pool (LIP), an excess of Fe²⁺ poses a significant ROS risk as it can instigate damage to DNA, proteins, and lipids thereby eliciting cytotoxic effects and contributing to the pathogenesis of various diseases.⁴⁸

Fig. 4 Schematic illustration of intracellular iron ion-related chemistry reaction.

2.2.2 Fenton and lipid peroxidation reaction. The Fenton reaction, involving the interaction between Fe²⁺/Fe³⁺ and hydrogen peroxide (H₂O₂), is a critical process facilitated by superoxide dismutase (SOD).⁴⁹ Intracellular iron levels, particularly the presence of Fe²⁺, expedite the Fenton reaction resulting in the formation of deleterious hydroxyl radicals (˙OH).⁵⁰ Ferroptosis, characterized by lipid peroxidation, is a deviation from the glutathione peroxidase 4 (GPX4) pathway, and membrane lipids undergo oxidative modification through the Fenton reaction.⁵¹ This divergence is triggered by specific induction conditions, such as cystine deprivation or an excess of Fe²⁺.^52,53 During this process, Fe²⁺ serves as an electron donor, facilitating the generation of lipid ROS. The surplus of Fe absorption, surpassing ferritin storage capacity, may catalyze the formation of free radicals within cells and lead to damage across essential biomolecules.

Lipid peroxidation denotes the dioxygenation process leading to the formation of lipid (hydro)peroxides.⁵⁴ Mitochondria, serving as key regulators of OXPHOS, are pivotal in iron metabolism and homeostasis.⁵⁵ Mitochondrial iron is primarily involved in two critical processes: Fe–S cluster proteins and heme synthesis.⁵⁶ The accumulation of lipoylated enzymes and depletion of Fe–S cluster proteins in mitochondria leads to cuproptosis. Additionally, a pool of free Fe²⁺ exists within mitochondria, actively contributing to the accumulation of mitochondrial ROS (mitoROS). Hence, the accrual of iron within mitochondria is linked to the induction of mitochondrial dysfunction. The resulting lipid peroxidation within the mitochondria yields lipid hydroperoxides and reactive aldehydes, including malondialdehyde and 4-hydroxynonenal.^54,57

Iron is a crucial trace element vital for enzymatic activity, certain iron-containing proteins exhibit the capacity to generate substantial levels of ROS. Specifically, Fe²⁺ acts as a cofactor for lipoxygenase (LOX), an enzyme implicated in the peroxidation of polyunsaturated fatty acids (PUFAs).⁵⁸ LOXs are non-heme iron-dependent dioxygenases with a substrate preference for PUFAs direct oxygenation, and they extend this activity to PUFA-containing lipids within biological membranes. This observation raises the possibility that LOXs might serve as mediators in ferroptosis. Enzymes housing [4Fe–4S] clusters become susceptible to attack by ROS, resulting in the transformation of these clusters into [3Fe–4S] configurations. This conversion process is accountable for the liberation of labile iron and subsequent enzyme inactivation.⁵⁹ The cytotoxic potential of labile iron underscores its deleterious impact on cellular components, with both labile iron and ROS-generating iron-containing enzymes posing threats to DNA, lipids, and proteins. This toxicity, exacerbated by ROS from iron-containing enzymes, leads to oxidative stress that predominantly triggers apoptosis and ferroptosis via ROS signaling.

2.2.3 Tricarboxylic acid cycle reaction. The TCA cycle is integral to facilitating electron transport activities within protein complexes situated in the inner mitochondrial membrane (IMM).⁶⁰ Glutamine (Gln) assumes a critical role as an anaplerotic metabolite, fueling the mitochondrial TCA cycle, thereby elevating mitochondrial respiration rates consequently leading to heightened ROS generation. Mitochondrial processes, specifically TCA cycle and the electron transport chain (ETC), contribute to ferroptosis by generating lipid ROS.^61,62 Inhibition of the mitochondrial TCA cycle, ETC effectively alleviates mitochondrial membrane hyperpolarization, lipid peroxide buildup, and ferroptosis in cells.⁶³ This observation implies a potential interconnection between the inhibition of these metabolic pathways and the mitigation of detrimental cellular effects. Disruption of glutaminolysis can be mitigated by supplementing the TCA cycle with metabolites, such as α-ketoglutarate (αKG), succinate, fumarate, and malate.^52,64 These downstream metabolites of glutaminolysis can substitute for glutamine, mitigating lipid ROS accumulation in mouse embryonic fibroblasts (MEF) and HT-1080 cells.⁵¹ This finding further emphasizes the role of the TCA cycle in ferroptosis induced by cystine deprivation.⁶⁵

2.3 Copper

2.3.1 Homeostasis of copper. Serving as a cofactor, copper is integral to a spectrum of key metabolic enzymes that orchestrate various physiological processes (Fig. 5).⁶⁶ Within biological contexts, copper predominantly adopts oxidation states of cuprous (Cu⁺) and cupric (Cu²⁺).⁶⁷ However, different valencies of Cu possess different cellular activities. Significantly, extracellular Cu²⁺ intricately regulates the dynamic interplay between cell membrane receptors and growth factors. Upon translocation to cell membranes, Cu²⁺ undergoes reduction by metalloreductases. Subsequently, Cu⁺ is used to modify protein structure or phosphorylation status. This modification, in turn, influences the activation status of growth factor receptors on the plasma membrane. The cytoplasmic and nucleic Cu⁺ facilitate redox balance and regulate gene expression, respectively. Each cell type contains different concentrations of copper and utilizes it differently.⁶⁸ For example, [Cu] in hepatocytes are 20–69 μM in nuclei and 120 μM in the cytosol.⁶⁹ Dysregulation of copper levels has implications beyond mitochondrial respiration, affecting glycolysis, insulin sensitivity, and lipid metabolism.⁷⁰ Maintaining cellular copper within specific thresholds is imperative for preserving normal biochemical processes.⁷¹

Fig. 5 Schematic illustration of intracellular copper ion-related chemistry reaction.

2.3.2 Fenton-like reaction. The Fenton-like reaction represents a prevalent mechanism for Cu-catalyzed ROS generation.⁷² In this mechanism, Cu²⁺, under the influence of biological reductants, undergoes reduction to Cu⁺, enabling the catalytic breakdown of H₂O₂ through the Fenton-like reaction. This dynamic interplay involves the cyclic transition between Cu⁺ and Cu²⁺, culminating in the generation of highly reactive ˙OH. These radicals pose a significant oxidative risk (such as lipid peroxidation) and instigate DNA damage. Elevated levels of Cu-induced ROS are closely linked to impaired mitochondrial function. Additionally, the oxidative stress induced by surplus copper contributes to disruptions in lipid metabolism, leading to the deposition of lipids in the intimal layer.^73,74 In a noteworthy interaction, amyloid-β stimulates Cu-catalyzed oxidation, transforming ascorbate anion into an ascorbyl radical and subsequently generating reactive ˙OH via a Fenton-like reaction. Furthermore, copper induces glutathione oxidation via oxidative stress, diminishing the extent of glutathione conjugation and fostering the in vivo oxidation of catecholamines.⁷⁵

2.3.3 Copper-containing enzymatic reaction. Copper-containing enzymes are pivotal in various physiological processes.⁷⁶ Specifically, copper is directed to the mitochondria, which is integral to cytochrome oxidase (COX) and contributes significantly to OXPHOS and overall mitochondrial functionality.⁷⁷ Within the inner membrane, cytochrome C oxidase (CCO) operates as a key proton pump in the mitochondrial ETC.⁷⁸ Catalyzing the reduction of dioxygen, this enzyme concurrently couples the process with proton pumping, ultimately yielding the superoxide radical anion. The copper chaperone for COX17 is instrumental in the intracellular transport of copper, facilitating its movement from the cytoplasm to the mitochondrial intermembrane.^79,80 Subsequently, COX17 delivers these copper ions to the cysteine residues for the synthesis of CCO 1 (SCO1), thereby facilitating the formation of disulfide bonds. Notably, recent findings highlight the metalloreductase activity of ferredoxin 1, which reduces elesclomol-Cu²⁺ to free Cu⁺. This liberated copper ion is released into the mitochondrial copper pool, actively participating in the assembly of CCO or binding to lipoylated proteins, ultimately contributing to cellular cuproptosis. CCO critically enhances the proton motive force for ATP synthesis and employs oxygen as the terminal electron acceptor. Dysregulation in this process is a frequent cause of respiratory chain defects in humans.

Cu chaperone for superoxide dismutase (CCS) functions as a copper transport protein, facilitating the involvement of Cu⁺ in diverse physiological processes encompassing oxidation, protein synthesis, and protein secretion.⁸¹ Specifically, CCS acts as the mediator for copper delivery to superoxide dismutase 1 (SOD1).⁸² SOD1, also known as Cu, Zn-SOD, is an enzyme instrumental in the dismutation of superoxide radical anions, affecting their conversion into H₂O₂. In this catalytic role, SOD1 is integral to the regulation of intracellular ROS homeostasis.⁸³ Its precise function is paramount in preserving the integrity of essential biomolecules such as DNA, lipids, and proteins, against oxidative damage. Notably, the cytosolic presence of Cu, Zn-SOD holds great importance in safeguarding against ROS damage, especially concerning cardioprotection in ischemia-reperfusion injury.^84,85 During the mild formation of ROS in ischemic preconditioning, Cu, Zn-SOD assumes a significant regulatory role in modulating apoptosis.

2.3.4 Click reaction. Click chemistry facilitates specific labeling and probing of diverse biomolecules within living cells and animals, offering utility in drug design and in situ synthesis.^86,87 The Cu⁺-catalyzed azide–alkyne cycloaddition reaction (CuAAC) represents the prevailing form of click chemistry.⁸⁸ Notably, the CuAAC reaction has garnered considerable global attention for its efficacy in intracellular prodrug transformation.⁸⁹ In biological systems, Cu species act as catalysts, assuming a crucial role. Their frequent role as catalytic cofactors in enzymes is particularly notable, especially in processes related to antioxidant defense and diverse biochemical pathways.^90,91 Excessive Cu levels in the tumor microenvironment are instrumental in tumor development and metastasis. Utilizing the heightened [Cu] within tumor cells offers a unique avenue for the in situ generation of cancer-specific drugs through CuAAC. This approach enables targeted treatment while minimizing toxicity to normal cells. Xue et al. introduced a bioorthogonally catalyzed lethality (BCL) strategy employing CuAAC between the Ru-N₃ and mitochondria-targeting rhein-alkyne for in situ metallodrug synthesis within cancer cells.⁹² However, recent studies have highlighted the impact of oncogenes on intracellular glutathione metabolism, leading to a labile Cu⁺ deficiency. Addressing this challenge, Zhu et al. strategically augmented endogenous bioavailable Cu⁺ to catalyze the generation of anti-cancer drugs via CuAAC reaction, optimizing drug synthesis efficiency and inducing cancer cell apoptosis.⁹³

2.4 Zinc

2.4.1 Homeostasis of zinc. Zinc is an essential constituent of over 70 distinct metalloenzymes integral to diverse biological processes encompassing chemical reactions, metabolism, and immune response.²⁰ Its multifaceted roles include catalytic, structural, and regulatory functions. Additionally, Zn²⁺ plays a key role in safeguarding against metal toxicity and oxidative stress. Given its dual role as both an intracellular and intercellular messenger, zinc necessitates stringent control of its homeostasis (Fig. 6).⁹⁴ The distribution of intracellular Zn²⁺ is approximately 0.14 pM in mitochondria, 0.2 pM in the mitochondrial matrix, 0.9 pM–5 nM in the ER and 0.2 pM in the Golgi.⁹⁵ The transportation of zinc across biological membranes is under the governance of zinc-transporter proteins, known as ZnT (Zn transport) or ZIPs (Zrt- and Irt-like proteins).^96,97

Fig. 6 Schematic illustration of intracellular zinc ion-related chemistry reaction.

2.4.2 Zinc-containing enzymatic reaction. Functioning as a cofactor for over 300 proteins, zinc plays a pivotal role in diverse biochemical processes.⁹⁸ Its catalytic role is evident through zinc-containing enzymes,⁹⁹ which regulate crucial cellular processes, including but not limited to DNA synthesis, brain development, and normal growth. Metallothionein (MT) is a family of cysteine-rich proteins with a particular affinity for different metals, such as Zn²⁺ and Cu⁺.¹⁰⁰ The proposed role of MT extends to serving as a critical nexus between cellular Zn²⁺ levels and the redox equilibrium of the cell. Perturbation of this balance leads to the release of zinc from MT. MT2A interacts with homeobox-containing 1 (HMBOX1) to increase intracellular free [Zn²⁺], which inhibits apoptosis and promotes autophagy in human umbilical vascular endothelial cells.¹⁰¹ Moreover, ZIP 7 deletion in the intestinal epithelium and ZIP 10 deficiency in B cells induced apoptosis by increased ER stress and caspase activity, respectively.^102,103 ZnT-7 can inhibit hydrogen peroxide-induced apoptosis by reducing the aggregation of free Zn²⁺.¹⁰⁴ In contrast, ZIP 9-mediated testosterone treatment promotes apoptosis due to up-regulation of proapoptotic genes.¹⁰⁵ ZIP 8 and ZIP 14 facilitate more Fe²⁺ to be stored in the intracellular labile iron pool (LIP), which produces lipid peroxides to induce ferroptosis.¹⁰⁶ In addition, zinc aids in nutrient recovery by engulfing cells during lysosomal degradation of internalized entotic cells. This process involves a phosphoinositide kinase (PIK) containing an FYVE-type zinc finger.^107,108

2.4.3 Hyperphosphorylation. Intracellular Zn²⁺ signals intricately regulate protein phosphorylation. Elevated intracellular Zn²⁺ levels have been observed to activate extracellular signal-regulated kinase (ERK) and p38.¹⁰⁹ However, findings from these studies imply that the influence of Zn²⁺ on these kinases is mediated through an upstream target in the signaling cascade, rather than a direct effect. Zinc has been identified as a regulator of tau phosphorylation, exhibiting dual effects on tau protein dynamics. At elevated dietary zinc concentrations (250 μM), Zn²⁺ activates the Ras-Raf/mitogen-activated protein kinase/ERK pathway, leading to tau Ser214 phosphorylation, which, in turn, disrupts microtubule polymerization.¹¹⁰ Concurrently, zinc exacerbates tau toxicity through direct binding. For example, zinc induces phosphatase 2A inactivation and promotes tau hyperphosphorylation through an Src-dependent pathway.¹¹¹ Conversely, a reduction in Zn²⁺ concentration to 100 μM has been observed to induce the dephosphorylation of tau.

2.4.4 Oxidative stress. Zinc has been demonstrated to have preventive effects against oxidative stress-induced diabetes and serves as a protective factor against alcohol-induced liver damage.¹¹² Existing studies highlight that zinc deficiency amplifies ROS production, culminating in oxidative damage to pivotal biomolecules. The adverse consequences of ROS-induced damage are evidenced by heightened carbon-centered radicals in liver microsomes, accompanied by increased lipid peroxidation. Elevated oxidative stress can ensue from compromised activity in pivotal antioxidant enzymes housing zinc, including Cu, Zn-SOD, and the Zn–MT complex. Notably, the wild-type SOD1 initiates ER stress by inducing a ZnT under Zn deficiency.¹¹³ The MT scavenges Zn under extreme Zn deprivation. The observed surge in oxidative stress is ascribed to a dual phenomenon: the diminished activities of antioxidant enzymes and the augmented generation of ROS. As observed through magnetic resonance imaging, zinc deficiency has been associated with increased blood–brain barrier (BBB) permeability and culmination of oxidative stress.¹¹⁴ Numerous in vivo and in vitro investigations have highlighted the potential of the zinc–histidine complex to prevent ischemic injury, a phenomenon often instigated by ROS.

2.5 Other intracellular metal ions

Several other intracellular metal ions are proposed as essential for physiological functions (Fig. 7). Mg, the second most abundant intracellular metal, functions as a calcium channel blocker, modulating vasodilation, bronchodilation, acetylcholinesterase release, and anti-inflammatory responses.¹¹⁵ Mn and Co are redox-active transition metals, participate in the Fenton reaction, and are crucial components of numerous enzyme-active centers enabling chemical reactions at physiologically compatible rates.^116,117

Fig. 7 Schematic illustration of intracellular manganese, cobalt, and magnesium ions-related chemistry reaction.

Mg ions exhibit an oxidation state +2 and coordinate with six oxygen donor atoms.¹¹⁸ Mg²⁺ is indispensable for enzymes that catalyze ATP-dependent reactions. As a physiological antagonist to Ca, the Mg/Ca ratio significantly influences the activity of Ca-ATPases and other calcium transport proteins. Mild fluctuations in cellular magnesium levels can alter calcium signaling or lead to toxicity.¹¹⁹ Therefore, elucidating the pathways and mechanisms of Mg²⁺ transport is vital for advancing therapeutic strategies against cancer and related pathologies.

Mn exists in biological systems in oxidation states ranging from +2 to +4, adopting various coordination geometries and contributing to oxidation reactions.^120,121 Mn can be transported from the bloodstream into cells via voltage-regulated or glutamate-activated calcium channels. Mn-SOD (SOD2) in mitochondria is pivotal for increasing gene expression linked to radiation-induced adaptive responses and is influenced by tumor protein p53 (TP53 or p53), underscoring its significance in cancer mechanisms and treatment strategies. Pyruvate carboxylase is a mitochondrial enzyme that facilitates the conversion of pyruvate to oxaloacetate and involves a biotin group and Mn²⁺ or Mg²⁺. Furthermore, arginase is an Mn-dependent enzyme in the urea cycle that processes L-arginine into urea and L-ornithine.¹²² Given the multifunctional role of Mn, its homeostasis is critically maintained to prevent toxicity while ensuring its biological availability.

Co is crucial for forming the Co–C bond in the coenzyme vitamin B12; however, excessive Co is carcinogenic.^123,124 Its standard oxidation states are +2 and +3. It disrupts DNA repair and promotes damage through cobalt-catalyzed free radical generation via the Fenton reaction. In the presence of SOD, Co contributes to oxidative stress by reacting with dioxygen, forming ˙OH through cobalt peroxy radicals (Co⁺-OO˙). Co and Mn can occupy the same nonheme site, influencing heme-copper oxidase activity in heme-nonheme biosynthetic myoglobin models. Furthermore, cobalt can substitute zinc in Zn-dependent enzymes and increase the activity of certain liver enzymes like heme oxidase.

Perturbations in intracellular metal ion homeostasis can trigger chemical reactions and influence diverse physiological functions. Table 1 briefly summarizes the representative intracellular metal ions and their corresponding chemical reactions, key pathways, and major localization. This understanding inspires a promising cancer treatment strategy by intentionally disrupting metal ion homeostasis to destabilize tumor environments. In addition, intracellular metal ions are mechanistically linked to diverse PCDs. Therefore, it is promising to investigate how to leverage intracellular metal ions to treat cancer by PCD.

Table 1 Representative intracellular metal ion-based chemical reactions

Metal ion		Reaction category	Key pathways	Major localization	Ref.
Calcium		Enzyme activation, signal transduction	RyR, IP3R; TRPM2, CaMKII	Endoplasmic reticulum, mitochondria, nuclear	21–26
Iron		Fenton and lipid peroxidation reaction, TCA cycle	Fe with H2O2, GSH oxidation, GPX4, Fe–S, LOX; glutamine, ETC	Mitochondria, lysosomes, cytosol, nuclei	45–47,49–51,54,61
Copper		Fenton-like reaction, copper-containing enzyme catalysis, click reaction	Cu with H2O2, GSH oxidation; COX, CCO, SCO1, CCS	Mitochondria, nuclei, cytosol	66–71,86,87
Zinc		Zinc-containing enzyme catalysis, hyperphosphorylation, oxidative stress	MT, ZnT, ZIP; p38, ErK, Sec/PP2A; NADPH oxidation	Mitochondria, nuclei, cytosol, golgi apparatus	20,95–98
Others	Cobalt	Fenton-like reaction	Co with H2O2, SOD, B12	Cytosol, nuclei,	116,117
	Magnesium	ATP-dependent catalysis	ATP, pyruvate carboxylase	Mitochondria, nuclei, endoplasmic, sarcoplasmic reticulum	118,119
	Manganese	Fenton-like reaction	Mn with H2O2, GPX4, SOD2, pyruvate carboxylase, arginase	Mitochondria, lysosome, cytosol, golgi apparatus	120–122

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3. Programmed cell death in cancers

3.1 Apoptosis

Apoptosis represents the principal cellular death pathway actively involved in developmental processes and the maintenance of tissue homeostasis.^125,126 Apoptosis is the biological mechanism responsible for the removal of damaged or superfluous cells from the body.^127,128 This process is characterized by a well-organized sequence of events, including cellular condensation, nuclear fragmentation, and nucleolysis, leading to the demise of apoptotic cells. The induction of apoptosis is governed by the precise regulation of key signaling pathways and targets,¹²⁹ which encompass tumor necrosis factor (TNF)-related ligands and receptors, B cell lymphoma 2 (BCL-2) family members, apoptotic peptidase activating factor 1 (APAF1), cytoC, the nuclear factor-kappa B (NF-κB) pathway, and p53, among others.¹³⁰ Notably, the transfer of Ca²⁺ from the ER to mitochondria emerges as a prerequisite for specific apoptotic stimuli. The redox-active transition metals (Fe, Cu, Mn, and Co) and Zn²⁺ emerge as potent inducers of ROS generation to trigger apoptosis by the Fenton reaction. Failure to regulate or resist this process often results in tumorigenesis. To this end, a Cu⁺-catalyzed click reaction was able to activate apoptosis by the generation of an anti-tumor drug (Fig. 8(a)).⁹³ Hence, the meticulous modulation of the apoptotic signaling pathway emerges as a pivotal approach to enhancing cancer treatment.

Fig. 8 The application of PCD in cancer cells. (a) Schematic of an endogenous copper(I)-based bioorthogonal catalysis system for cancer therapy by apoptosis. Reproduced with permission.⁹³ Copyright 2023, American Chemical Society. (b) Diagram the transferrin and the glutaminolysis is required for ferroptosis.⁶⁰ Reproduced with permission. Copyright 2015, Elsevier. (c) Schematic diagram of two nanoreceptors within the cytoplasm, binding mutant p53 protein and inducing autophagy. Reproduced with permission.¹³¹ Reproduced with permission. Copyright 2024, Springer Nature. (d) Illustration of preparation of a ZPHM nanoregulator and the boosted pyroptosis for cancer therapy. Reproduced with permission.¹³² Copyright 2023, American Chemical Society.

In apoptosis, two main pathways—intrinsic and extrinsic—are governed by caspases, a family of cysteine proteases.¹³³ Intrinsic apoptosis is instigated by disturbances within the cellular microenvironment, such as DNA damage, ER or oxidative stress, and cytosolic calcium overload. MOMP is governed by a balance in the BCL-2 protein family.¹³⁴ Certain anti-apoptotic members of the BCL2 family are believed to promote cellular survival through various mechanisms. These mechanisms include (1) regulating Ca²⁺ homeostasis within the ER, (2) boosting bioenergetic metabolism via F1FO ATP synthase interaction, and (3) maintaining redox homeostasis. However, extrinsic apoptosis is commonly initiated by death receptors (DRs) upon engagement with their respective ligands.¹³⁵ DRs, following ligand binding, facilitate the assembly of DISC (death-inducing signaling complex) and complex II, culminating in caspase-8 (CASP8) activation and subsequent extrinsic apoptosis.¹³⁶

Intrinsic apoptosis is pivotal in preventing oncogenesis, and dysregulation of this process has been implicated in numerous cancers, such as chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML).¹³⁷ Particularly, the upregulation of BCL2, BCL-XL, or MCL-1 accelerates leukemia and lymphoma development, often in conjunction with overexpression of the MYC proto-oncogene. The pharmacological targeting of BCL2 proteins effectively combats MYC-driven tumors, even when p53 function is impaired. Notably, p53 serves as a direct and indirect regulator of apoptotic gene expression and links apoptosis to cell cycle arrest.¹³⁸ Extensive research has unveiled the tumor-suppressive role of the intrinsic apoptotic pathway across a spectrum of cancer types.^139,140 Additionally, distinct roles within the BCL2 protein family have been ascribed to specific members in cancer. These results encourage researchers to investigate and better understand why the inhibition of apoptotic cell death promotes tumorigenesis in certain scenarios while inhibiting it in others.

Recent research has unveiled tumor-suppressive role of CASP8 in the liver and select tissues, impacting the DNA damage response and chromosomal instability in early-stage tumorigenesis.^141,142 However, TNF-R1 and Fas exhibit contrasting roles in hepatic and ovarian oncogenesis compared to other tumor types. TNF blockade attenuates hepatic cancer onset in experimental cholestatic hepatitis. Iron plays a pivotal role in regulating Fas-mediated extrinsic apoptosis by modulating alternative splicing in an iron-dependent manner.^143,144 The apparent variability in outcomes across different cancer models may be attributed to cancer-specific predilections for either apoptotic, necroptotic, inflammatory, or pro-invasive signaling pathways elicited by FasL.

3.2 Necroptosis

Necroptosis is governed by RIPK1 and can be induced by various triggers.^145–147 Significantly, it is intriguing to observe that the same ligands are responsible for initiating the extrinsic apoptosis pathway, either by caspase inhibitors like Z-VAD-FMK or by depleting Fas-associated death domain protein (FADD).¹⁴⁸ Notably, necroptosis is distinct from necrosis, as it strictly adheres to intracellular signaling regulation within cancer cells and involves active energy consumption.¹⁴⁹ RIPK3 phosphorylates mixed lineage kinase domain-like protein (MLKL), culminating in necroptosis characterized by disruption of the plasma membrane and cell lysis.¹⁵⁰ Necroptotic signaling serves a diverse function in tumorigenesis, necrosis, metastatic progression, and immune interactions.

Necroptosis is a common occurrence within the central regions of solid tumors, primarily attributed to inadequate vascularization leading to oxygen and nutrient deprivation. Recent research findings indicate deletion of MLKL leads to a substantial reduction in tumor necroptosis, with the remaining areas exhibiting a shift in cell death mode to apoptosis.¹⁵¹ The RIPK3 expression has a distinct pattern in various solid cancer cell lines, especially in human solid tumor models.^152,153 Notably, necroptosis mediated by RIPK3 can yield both anti-tumorigenic and pro-tumorigenic outcomes that are dependent on tumor type, stage, and progression.^154,155

3.3 Ferroptosis

Ferroptosis describes an iron-dependent, non-apoptotic form of PCD initiated by erastin.⁵¹ A defining feature of ferroptosis is cell mortality driven by iron-dependent lipid peroxide accumulation in mitochondria, alongside the deactivation of GPX4.¹⁵⁶ The functionality of GPX4 is intricately tied to glutathione (GSH), a molecule derived from cysteine and glutamate, which are regulated by the amino acid antiporter, system xc-. Three pivotal hallmarks categorize ferroptosis: (1) oxidative damage to membrane phospholipids containing polyunsaturated fatty acids (PUFA); (2) the availability of redox-active iron; (3) the diminished capacity to repair lipid hydroperoxides (LOOH).⁵⁴ Cells undergoing erastin-induced ferroptosis exhibit mitochondria with aberrant morphology, specifically reduced cristae and compromised outer membranes, evidenced by condensation and rupture.¹⁵⁷ The onset of ferroptosis is intimately tied to intracellular iron accumulation, free radical generation, fatty acid availability, and lipid peroxidation.^158,159 The overarching objective of elucidating the mechanistic underpinnings of ferroptosis is to enhance the spectrum of therapeutic avenues for cancer treatment.

Ferroptosis, functioning as an adaptive mechanism for the eradication of malignant cells, represents an emerging tumor-suppressing pathway.^160,161 For example, Interferon-γ, traditionally recognized for its inhibitory effect on system xc- activity, is secreted from CD8⁺ T-cells.¹⁶² This secretion leads to the suppression of both subunits of system xc- within tumor cells which further enhances the efficacy of cancer immunotherapy. Additionally, iron paves the way to produce ROS by the Fenton reaction (Fig. 8(b)).⁶⁰ Both traits make cancer cells particularly receptive to ferroptosis induction. Furthermore, the augmentation of cellular iron availability through the autophagic degradation of ferritin has been observed to promote ferroptosis. Conversely, mechanisms that facilitate the export of cellular iron have demonstrated the capacity to enhance cell resistance to ferroptosis.

Diverse cancer cell lines show an inherent sensitivity to ferroptosis, and a multitude of molecular mechanisms contributing to these susceptibilities. For instance, in p53-dependent cancers, ALOX12 can instigate ferroptosis independently of GPX4 function.¹⁶³ In addition, ACSL4-overexpressed cells display susceptibility to ferroptosis inducers erastin and RSL3, whereas ACSL4-deficient cancer cells exhibit high resistance.¹⁶⁴ The sensitivity or resistance of a specific cancer to ferroptosis induction is fundamentally governed by its distinct genetic landscape.

3.4 Autophagy-dependent cell death

Autophagy,¹⁶⁵ a type II PCD, comprises four fundamental stages: induction, involving the initiation of autophagy and formation of autophagic vesicles; autophagosome formation; fusion between autophagosomes and lysosomes; and lastly, the degradation occurring within the autolysosome.¹⁶⁶ Autophagy exhibits a dual role in tumor initiation and progression. During the early stages of tumor formation, autophagy serves as a safeguard by regulating and eliminating cancer cells. However, once tumors have developed, autophagy shifts its function to sustain the survival of tumors and facilitate their growth. The orchestration of the autophagic process involves a suite of key genes, including Unc-51-like kinase 1 (ULK1), p62, Beclin-1, forkhead box O (FoxO), light chain 3 (LC3), and other autophagy-related (ATG) genes.¹⁶⁷ Additionally, the phosphatidylinositol 3-kinase/protein (PI3K) kinase-B(Akt)/mammalian target of the rapamycin (mTOR) pathway is a crucial signaling cascade. Simultaneously, AMP-activated protein kinase (AMPK) serves as a pivotal energy sensor, regulating cellular metabolism and preserving energy equilibrium.¹⁶⁸ A significant contributor to autophagy regulation is the tumor suppressor p53, whose location determines its function.¹⁶⁹ Nuclear p53 enhances autophagy by activating upstream of mTOR, whereas cytoplasmic p53 inhibits autophagy. The precise function of autophagy in cancer remains a subject of ongoing debate. Moreover, elevated intracellular metal ions will simulate the autophagic regulators and induce the autophagic process.

Autophagy-dependent cell death represents a PCD type reliant on the autophagic machinery. The molecular machinery shows some differences with adaptative autophagy. Proficient autophagic responses primarily function at the core of stress adaptation, thereby conferring cytoprotective effects. Consequently, interference with autophagy, through pharmacological or genetic means, tends to expedite cellular death in response to stress. Furthermore, inherent or temporary defects in autophagy have been linked to conditions such as embryonic lethality, developmental anomalies, and a spectrum of pathological disorders, especially cancer. As numerous elements within the autophagy machinery serve functions distinct from autophagy, it is advisable to confirm the participation of a minimum of two distinct ATG proteins. Furthermore, in instances of autophagy-dependent cell death, when the inhibition of autophagy averts cell death, it is essential to provide substantiating evidence that rules out the involvement of other PCD modalities, including FAS-driven extrinsic apoptosis, necroptosis, and ferroptosis.

At a fundamental level, the cell-independent impact of autophagy is associated with tumor-promoting functions (Fig. 8(c)).^131,170 ULK1 is a multifunctional target that triggers the autophagy process. Both ULK1 inhibition and activation have substantial effects on tumor treatment outcomes.¹⁷¹ The inhibition of ULK1 to impede early autophagy has shown promise in suppressing cell growth and combatting drug resistance in tumor therapy.¹⁷² Conversely, ULK1 activation is associated with adverse tumor prognosis. This observation implies that activating ULK1 to induce autophagy may represent a promising therapeutic strategy for inhibiting tumor growth in select cancer types.

3.5 Pyroptosis

Pyroptosis,¹⁷³ a PCD mechanism with an associated inflammatory response, encompasses two pathways: the canonical pathway, mediated by caspase-1 (CASP 1), and the noncanonical pathway, involving caspase-4, 5, and 11.^174,175 Nod-like receptors (NLRs) or absent in melanoma 2 (AIM2)-like receptors (ALRs) instigate the assembly of inflammatory bodies in response to specific stimuli, culminating in the formation of activated CASP 1.¹⁷⁶ Conversely, lipopolysaccharide (LPS) induces the activation of caspase-4, -5, and -11.¹⁷⁷ These caspases cleave gasdermin-D (GSDMD) thereby instigating pyroptosis.¹⁷⁸ In both pyroptotic pathways, caspase-1/4/5 cleaves GSDMD protein, facilitating the conversion of pro-IL-1β and pro-IL-18 to their respective mature forms.¹⁷⁹ Conversely, GSDME is cleaved by caspase-3, resulting in pyroptotic death. These proteins create nano-scale pores (10 to 20 nm) in the cell membrane, facilitating the gradual release of cellular contents through these membrane apertures. Consequently, pyroptosis manifests through nuclear condensation, concurrent cell swelling, and substantial plasma membrane blebbing, ultimately leading to rupture.

Pyroptosis exhibits suppressive effects on the initiation and progression of cancers.^180,181 Robust evidence from diverse studies underscores the capacity of chemotherapeutic drugs, natural compounds, and specific reagents to instigate pyroptosis across various cancer types.¹⁸² Noteworthy examples include actinomycin-D, doxorubicin (DOXO), and bleomycin, which have demonstrated the ability to induce pyroptosis in lung cancer (LC) and melanoma cell lines.^183,184 Lobaplatin treatment demonstrates a notable capacity to induce pyroptosis in colorectal cancer (CRC) cell lines, evidenced by the cleavage of GSDMD and GSDME.^185,186 These findings lay the groundwork for understanding the diverse abilities of distinct chemotherapeutic agents in inducing pyroptosis across cancer cell lines expressing GSDME. Emerging nanomaterials designed to target pyroptosis show promise in tumor therapy. Recently, a bioorthogonal pyroptosis nanoregulator was shown to not only induce pyroptosis, but also disrupt the construction of checkpoints, presenting a significant advancement in the pursuit of safe and efficacious pyroptosis-based cancer therapy (Fig. 8(d)).¹³² These investigations provide innovative perspectives endorsing pyroptosis as a promising mechanism for eradicating oncogene-addicted tumor cells.

3.6 Cuproptosis

Cuproptosis is set in motion by an excess of Cu²⁺.^187,188 This Cu-induced PCD pathway stands apart from other cell death mechanisms. Intracellular copper ions exhibit a distinct affinity for fatty-acylated proteins within the tricarboxylic acid (TCA) cycle associated with mitochondrial respiration, leading to consequential fatty-acylation modifications.¹¹ The accumulation of lipoylated mitochondrial proteins bound to copper, in conjunction with the subsequent depletion of Fe–S clusters, imposes proteotoxic stress, culminating in cell demise. The elucidation of the cuproptosis mechanism paves the way for future drug research, with a specific focus on copper ionophores and compounds associated with cuproptosis.^71,189 These findings introduce novel perspectives on potential applications in cancer treatment. Disulfiram (DSF) and elesclomol (ES) have emerged as focal points of research and have been the subject of clinical trials. DSF, when combined with Cu²⁺, demonstrates noteworthy anti-tumor activity across diverse cancer types.¹⁹⁰ The gene most significantly linked to ES sensitivity, Ferredoxin 1 (FDX1), was identified as a direct target of ES–Cu.¹⁹¹ ES–Cu binding directly inhibits FDX1 function in Fe–S cluster formation. Ammonium tetrathiomolybdate (TTM) effectively counteracts these changes in mitochondrial membrane potential.¹⁹² ES triggers cell death through the translocation of copper ions into both cells and mitochondria, thereby increasing intracellular copper ion levels. This, in turn, leads to dihydrolipoamide S-acetyltransferase (DLAT) oligomerization, diminished Fe–S stability, and interaction with Npl4.^193,194 These discoveries suggest that the intracellular delivery of copper via ionophores holds promise as a therapeutic approach for specific tumor subtypes.

3.7 Entotic cell death

Entotic cell death (Entosis), a manifestation of cell cannibalism, is marked by the engulfment and demise of one cell by another.¹⁹⁵ Initially identified in human mammary epithelia, then this phenomenon is prevalent in epithelial and other human tumors.¹⁹⁶ Central to the regulation of entosis induction are the pathways governing cell adhesion and cytoskeletal rearrangements. Entosis is distinguished by the digestion of engulfed cells by host cells, a process independent of BCL2 proteins and caspases. Instead, it predominantly relies on LC3-associated phagocytosis (LAP) and lysosomal degradation pathway mediated by cathepsin B (CTSB).^197,198 LAP serves as an intermediary linking phagocytosis and autophagy.^199,200 The recruitment of the essential LC3 lipidation machinery, comprising ATG5, ATG7, PIK3C3, and PIK3 regulatory subunit 4 (PIK3R4), to the cytosolic aspect of vesicles containing entotic cells is instrumental in facilitating their fusion with lysosomes.

Entosis is facilitated by cell-in-cell structures and has been observed across various cancers, such as breast, colon, and pancreatic carcinoma (PACA).^201,202 Entosis can impede tumor advancement by inducing death in internalized cells, while concurrently, may foster tumor progression by promoting competition between tumor cells. Thus, entosis presents a dualistic role in tumorigenesis, characterized by both tumor-inhibitory and tumor-promoting effects. It functions as an inhibitor by eliminating matrix-detached tumor cells, impeding the advancement of tumors. Conversely, it may contribute to tumor progression through its ability to induce changes in cell ploidy.²⁰³ This disruption leads to the formation of binucleate-engulfing cells. Consequently, entosis is identified as a cell death process with notable involvement in critical biological events associated with cancer.

3.8 Netotic cell death

Netotic cell death (NETosis), instigated by neutrophil extracellular traps (NETs) release, stands as a distinct form of PCD.²⁰⁴ NETs are released by activated neutrophils, but other epithelial cells can also generate NETs in response to diverse stresses, such as leukocyte populations, and cancer cells. NETosis is a dynamic process involving nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)-driven ROS generation, the induction of autophagy, and the release/translocation of granular enzymes and peptides, mainly belonging to the cathelicidin family.²⁰⁵ NETosis occurs via NOX-dependent and NOX-independent mechanisms, and the specific mechanism is dependent on the inducer. NOX-dependent NETosis is triggered by agents like phorbol 12-myristate 13-acetate and LPS, which promote NOX assembly and ROS production, thereby initiating NETosis.²⁰⁶ Conversely, NOX-independent NETosis is instigated by ionomycin, which induces NETosis through Ca overload without NOX activation.²⁰⁷ This overload activates PAD4, leading to histone citrullination, while Gasdermin D contributes to chromatin decondensation, nuclear disintegration, and cell rupture.^208,209

The formation of neutrophil NETs occurs within the tumor microenvironment.²¹⁰ Malignant tumors can secrete granulocyte colony-stimulating factor (G-CSF) to promote NETosis.²¹¹ Upregulation of G-CSF correlates with an increased neutrophil count in the bloodstream, leading to ROS production and subsequent NET formation. NETosis has emerged as a potential contributor to the reawakening of dormant tumor cells, playing a pivotal role in tumor recurrence and metastasis. Thus, NETosis exhibits dualistic characteristics, manifesting both tumor-promoting and antitumor effects. The outcome is contingent upon the immune system's status and the dynamic interplay within the tumor microenvironment.²¹² Consequently, there is an imperative need to channel further research into finely balancing the regulation and occurrence of NETosis.

3.9 Parthanatos

Poly(ADP-ribose)polymerase-1 (PARP-1)-dependent cancer cell death is a novel form of PCD termed “parthanatos.”²¹³ Parthanatos is instigated in response to oxidative stress, inducing DNA damage and chromatin degradation. While it shares certain characteristics with necroptosis, autophagy, and apoptosis, the underlying molecular mechanisms of NETosis are distinct. Noteworthy features of parthanatos include plasma membrane rupture, the prompt activation of PARP-1, early poly ADP-ribose (PAR) accumulation,^214,215 depletion of cellular nicotinamide adenine dinucleotide (NAD⁺) and ATP, mitochondrial depolarization, apoptosis-inducing factor (AIF) release from the mitochondria, recruitment of migration inhibitory factor (MIF), nuclear translocation of the AIF/MIF complex, and DNA fragmentation following DNA damage.²¹⁶ Consequently, the pivotal events in parthanatos entail the transduction of PAR polymer signaling to the mitochondria and the translocation of AIF from the mitochondria to the nucleus.

PARP-1 has a multifaceted role in tumorigenesis. The clinical implementation of PARP-1 inhibitors has exhibited favorable outcomes in specific cancer types and among individuals with distinct genetic susceptibilities.²¹⁷ PARP-1 serves as a DNA damage receptor during tumorigenesis, rapidly activating its enzyme activity following DNA damage, culminating in pronounced PARP-1 activity and eventual parthanatos.²¹⁸ Elevated levels of PARP-1 have been observed in BC,²¹⁹ ovarian cancer (OC),²²⁰ and head and neck cancer (HNC)²²¹ tissues in comparison to their normal counterparts, underscoring the intimate association between parthanatos and these malignancies. Conversely, studies have revealed that PARP-1 knockout mice exhibit a substantially reduced risk of epithelial cancer.²²² Presently, clinical cancer treatment has benefited from the approval of four PARP inhibitors: olaparib,²²³ rucaparib,²²⁴ niraparib,²²⁵ and talazoparib.²²⁶ Among them talazoparib exhibits superior efficacy, particularly in advanced BC.²²⁷ Given the integral role of PARP-1 in multiple DNA repair pathways and genomic stability maintenance, the regulation of PARP-1 activity emerges as a vital clinical strategy for interventions in related cancers.²²⁸

3.10 Lysosome-dependent cell death

Lysosome-dependent cell death (LDCD) is characterized by the destabilization of lysosomes and necessitates lysosomal membrane permeabilization (LMP).²²⁹ Lysosomes, acidic cellular organelles, are proficient in degrading diverse cargos derived from heterophagy and autophagy processes.²³⁰ Lysosomes undergo LMP when exposed to lysosomotropic detergents, ROS, dipeptide methyl esters, and lipid metabolites.^231,232 ROS, notably via H₂O₂-driven luminal hydroxyl radical production in Fenton reactions and the resultant lipid peroxidation, assume a pivotal role in destabilizing the lysosomal membrane during LMP.²³³ Additionally, ROS facilitates the activation of lysosomal Ca²⁺ channels, namely TRPM2.²³⁴ As cell death executioners, cathepsins play varied roles in different contexts.²³⁵ The specific cathepsins involved in initiating and executing LCD depend on the context of LMP. Inhibiting cathepsin expression or activity effectively impedes LCD. Nevertheless, cathepsins do not singularly govern LCD, as this cellular demise pathway can manifest diverse features, such as apoptotic, necrotic, autophagic, or ferroptosis-like characteristics, contributing to the intricate landscape of LCD.²³⁶

The lysosome, acting as a central regulator, plays a crucial role in meeting catabolic demands for growth and supporting neoplastic anabolic processes.^237,238 Numerous agents designed to disrupt lysosomal function are currently subjects of investigation or in various stages of clinical development for cancer therapy. One notable example is chloroquine, which induces LMP to modulate lysosomal function.²³⁹ This, in turn, has the potential to reinstate sensitivity to cisplatin in non-small cell lung cancer cells that had exhibited resistance. These findings point to an increased fragility of lysosomes in tumor cells relative to normal cells, predisposing them to LMP and subsequent LDCD.²⁴⁰ Hence, it is imperative to gain a comprehensive understanding of the intricate regulatory processes governing LMP in cancer cells in order to leverage LDCD for cancer therapy.

3.11 Alkaliptosis

Alkaliptosis, identified as a newly recognized pH-dependent form of PCD,²⁴¹ demonstrates robust anti-tumor efficacy, notably against pancreatic ductal adenocarcinoma.²⁴² Song et al. screened 254 G-protein-coupled receptors (GPCRs)-interacted compounds to identify a GPCR-targeted small molecule JTC801 with cytotoxic activity against a human pancreatic cancer (PC) cell line. The anticancer mechanism attributed to JTC801 is specifically associated with the induction of alkaliptosis, distinguishing it from apoptosis, necroptosis, ferroptosis, and autophagy-dependent cell death. Notably, the alkaliptosis-inducing properties of JTC801 exhibit promise as a selectively lethal agent for tumor cells, devoid of significant side effects.²⁴² Alkaliptosis, marked by a fatal elevation in intracellular pH, is orchestrated by the coordinated activity of ion channels as well as transporters within both intracellular and extracellular pathways.^243,244

Intracellular alkalization-dependent alkaliptosis emerges as a promising cell death mechanism for cancer therapy, especially in drug-resistant cancers.²⁴⁵ In human PC cells, the heightened expression of ATP6V0D1 has been identified as a facilitator of JTC801-induced alkaliptosis, showcasing a distinct interaction with STAT3. This underscores the pro-death role of ATP6V0D1 in alkaliptosis, offering insights for the development of PCD strategies in tumor treatment.

3.12 Oxeiptosis

Oxeiptosis, characterized as a ROS-induced noninflammatory PCD, operates independently of caspases.²⁴⁶ The key mediators in the oxeiptotic process include kelch-like ECH-associated protein 1 (KEAP1), PGAM family member 5 (PGAM5), and AIFM1.²⁴⁷ The KEAP1-NFE2L2 pathway is recognized for orchestrating cytoprotective responses in the face of oxidative injury when ROS concentrations are low. In contrast, heightened ROS concentrations prompt KEAP1 to disengage from PGAM5 and engage in an interaction with AIFM1, instigating death signaling.

Recent investigations have unveiled that macrophages can instigate oxeiptosis in mesothelioma cells by activating PGAM5 through a ROS-dependent mechanism. Notably, sanguinarine has emerged as an efficacious agent in curtailing tumor growth in human CRC cells.²⁴⁸ This suppression occurs through the induction of oxeiptosis, driven by ROS, with a specific focus on H₂O₂-dependent activation of the KEAP1-PGAM5-AIFM1 pathway.²⁴⁹ Moreover, alloimperatorin has been identified as a modulator of the Keap1/PGAM5/AIFM1 pathway, facilitating oxeiptosis and effectively hindering the survival of BC cells.^250,251

As shown in Table 2, twelve representative PCDs capable of inducing different types of cancer cell demise through specific targets have been briefly summarized, including their key regulator molecules and the corresponding intracellular metal ions. However, some PCDs that are triggered by intracellular metal ions have yet to be further explored. Collectively, the relationship between intracellular metal ions and PCD remains to be further investigated.

Table 2 Morphological features of representative cell death pathways induced by intracellular metal ions

Cell death mode	Morphological features	Key regulators	Cancer cell line	Metal ion	Ref.
Apoptosis	Cell and nuclear condensation, apoptotic body formation	BCL-2 family (BAX/BAK, BOX, BCL2, BID), p53, Caspase-2/8/9/10, Caspase-3/6/7, APAF1, NF-κB	Lung cancer, gastric cancer, prostate cancer	Ca, Fe, Cu, Zn, Co, Mg	127–130,133,134
Necroptosis	Cell swelling, nuclear chromatin loss, plasma membrane rupture	RIPK-1, RIPK-3, MLKL	Colon cancer	Fe	145–153
Ferroptosis	Cell swelling, mitochondrial condensation and rupture, plasma membrane collapse	GPX4, SLC7A11, ALOX12/15, ACSL4, NCOA4	Triple-negative breast cancer, colorectal cancer	Ca, Fe, Cu, Co, Mn	51,156–164
Autophagy-dependent cell death	Autophagosomes and lysosomes formation, autophagosome–lysosome fusion	ULK1, p62, Beclin-1, FoxO, LC3, ATG, p53, PI3K/Akt	Breast cancer	Ca, Cu, Zn	131,165–172
Pyroptosis	Nuclear condensation, cell swelling, plasma membrane rupture, bubbling, chromatin fragmentation	Caspase-1, Caspase-4, Caspase-5, Caspase-11, GSDMD, GPX4, ESCRT-III	Human melanoma, colon cancer, lung cancer, breast cancer, gastric cancer, hepatocellular carcinoma	Ca, Fe, Mn	132,173–186
Cuproptosis	Cell swelling, chromatin fragmentation, mitochondrial condensation	P53, FDX1, DLAT, glutamine	Glioblastoma, non-small cell lung cancer	Cu	187–194
Entosis	Cell-in-cell structure	ATG5, ATG7, PIK3C3, PIK3	Breast cancer, colon cancer, pancreatic cancer		195–202
Netosis	Nuclear swelling, plasma membrane rupture, chromatin fiber release	PAD4, MPO, NAPDH/ROS	Pancreatic cancer		204–211
Parthanatos	Nuclear condensation, membrane rupture, large DNA fragmentation	PARP-1, AIF, MIF	Breast cancer, ovarian cancer, head and neck cancer, epithelial cancer		213–222
Lysosome-dependent cell death	Lysosome and plasma membrane rupture	Cathepsins, p53	Non-small cell lung cancer	Ca, Zn	229–240
Alkaliptosis	Necroptosis-like morphology	NF-κB, STAT3	Pancreatic ductal adenocarcinoma, prostate cancer		241–245
Oxeiptosis	Apoptosis-like morphology	KEAP1, PGAM5, AIFM1	Mesothelioma, colorectal cancer, breast cancer		246–251

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4. Intracellular metal ion-triggered programmed cell death

PCD represents a promising strategy for the eradication of cancer by orchestrating the process of PCD that is integral to maintaining cellular homeostasis by disposing of aged, impaired, or undesirable cells.²⁵² The pervasive role of intracellular metal ions as universal cell signaling entities underscores their regulation of numerous physiological activities across all biological domains. Consequently, exploring intracellular metal ion dyshomeostasis is poised to provide novel insights into PCD.²⁵³ This discussion primarily focuses on Ca²⁺, Fe^2+/3+, Cu^+/2+, Zn²⁺, elucidating their interplay in different signaling pathways in PCD.²⁵⁴

4.1 Calcium-triggered programmed cell death

The [Ca²⁺]i, as a ubiquitous second messenger, plays a pivotal role in PCD, especially in the pathogenesis and progression of tumors.²⁵⁵ Notably, dysregulation in [Ca²⁺]i homeostasis emerges as a critical determinant influencing proliferation, invasion, and metastasis within cancerous tissues.²⁵⁶ The depletion of ER Ca²⁺ stores plays a crucial role in the regulation of diverse cellular processes, encompassing cell growth, proliferation, exocytosis, enzymatic activity and motility modulation, and immune responses. A prevalent observation notes the swift escalation of cytoplasmic Ca²⁺ concentration in response to oxidative stress across diverse cell types. This necessitates an examination of the roles of Ca²⁺ transport systems within the ER and mitochondria in cellular fate. Like other intracellular second messengers, calcium possesses a dose-dependent capacity to induce hormesis or cell death processes, such as apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy-dependent cell death, and so on (Fig. 9).^257–259

Fig. 9 Schematic signaling pathway of representative calcium-triggered programmed cell death.

4.1.1 Calcium-triggered apoptosis. The sarco/endoplasmic–reticulum Ca²⁺-ATPase (SERCA) emerges as a pivotal regulator of cell death processes, holding the distinction of being the foremost primary ER-resident protein.²³ Down-regulation of SERCA attenuates the apoptotic response by curbing Ca²⁺ transfer, while heightened SERCA pump activity correlates with cell death. Another primary ER-resident protein family bifurcates into RyRs and IP₃Rs sub-groups.^23,260 A strategic focus on the ER-mitochondria Ca²⁺ interconnection emerges as a prospective avenue for reinstating apoptosis sensitivity in tumor cells. The intrinsic apoptosis pathways are critically influenced by mitochondrial Ca²⁺ overload, which functions as a key sensitizing signal. The mitochondrial network remodeling machinery, exemplified by Mitofusin 2 (MFN2), modulates mitochondrial Ca²⁺ uptake in response to IP₃-inducing stimuli.²⁶¹ This regulatory effect is evident through the reduced efficiency of mitochondrial Ca²⁺ uptake observed upon the ablation or silencing of MFN2 in fibroblasts and HeLa cells.

Significantly, [Ca²⁺]i signaling pathways exhibit dual roles, with IP₃R-mediated signaling promoting proliferation and oncogenic processes, whereas ryanodine receptor (RyR)-mediated signaling has been identified as a pro-apoptotic mechanism, particularly in lung cancer cells.²⁶² Ca²⁺-mediated apoptosis is induced by Bcl-2 IP₃ receptor disrupter-2 (BIRD-2), a phenomenon previously documented in lymphoid malignancies, and subsequently in diffuse large B-cell lymphoma marked by heightened Bcl-2 expression.^263,264

4.1.2 Calcium-triggered pyroptosis. Pyroptosis, an inflammatory form of PCD, is implicated in the progression of various diseases, such as cancer and neurological disorders. NLRP3 and caspase-3 stand as pivotal elements in the pyroptosis pathway. Lidocaine, a recognized regulator of this pathway, amplifies cytosolic Ca²⁺ flux, consequently instigating pyroptosis.²⁶⁵ The repression of CaMKII expression has been linked to a reduction in lidocaine-induced pyroptosis markers, such as caspase-3 and GSDME.²⁶⁵ Meanwhile, CaMKII plays a regulatory role in mitochondrial Ca²⁺ homeostasis, with its overactivation being associated with the induction of mPTP opening. The calcium-sensing receptor (CaSR),²⁶⁶ belonging to the GPCR superfamily, exerts regulatory control over various downstream signaling pathways influencing cellular fate.²⁶⁷ Specifically, CaSR-mediated pyroptosis increases in response to chromium(VI) accumulation.²⁶⁸ Noteworthy is the independent activation of the NLRP3 inflammasome by various DAMPs, despite the involvement of CaSR. Interestingly, CaSR has been identified as a regulator of the NLRP3 inflammasome, acting through Ca²⁺ and cAMP signaling. In addition, the clustering of translocated intimin receptor (Tir) is implicated in precipitating rapid calcium influx, leading to lipopolysaccharide (LPS) internalization, followed by the activation of caspase-4 and subsequent induction of pyroptosis.²⁶⁹

4.1.3 Calcium-triggered ferroptosis. The significance of Ca²⁺ in cell death processes is associated with oxidative glutamate toxicity analogous to ferroptosis.²⁷⁰ In contemporary investigations, compounds-based on erastin established inhibitory effects on oxidative glutamate toxicity, achieved through mechanisms such as the suppression of mitochondrial ROS generation, 12/15 lipoxygenase activity, or Ca²⁺ influx, confer cellular protection against treatments involving either erastin—an established inducer of ferroptosis—or sulfasalazine, another ferroptosis inducer via system xc- inhibition.^271,272 ESCRT-III (endosomal sorting complex required for transport III), activated by Ca, is implicated in membrane repair, cell death prevention, and immune modulation in ferroptosis. Studies indicate that ESCRT-III contributes to ferroptosis resistance. Downregulation of its components, CHMP4B, CHMP5, or CHMP6, increases susceptibility to ferroptosis in human cancer cells.^273,274 Calcium oxalate (CaOx) crystals have been implicated in the mediation of ferroptosis through modulation of the Nrf2/HO-1 and p53/SLC7A11 pathways.²⁷⁵ Consequently, this process diminishes the resilience of HK-2 cells to oxidative stress and other adverse conditions, leading to heightened cellular damage.

4.1.4 Calcium-triggered autophagy-dependent cell death. Elevated [Ca²⁺]i induces the accumulation of autophagic vesicles, thereby stimulating autophagy. This process is mediated through the activation of Ca²⁺/calmodulin-dependent protein kinase β (CaMKKβ)/AMPK and the concurrent inhibition of mTORC1.²⁷⁶ Conversely, the use of a cytoplasmic Ca²⁺ chelator effectively impedes autophagic vesicle accumulation, reinforcing the essential role of Ca²⁺ in autophagy stimulation. Additionally, bufalin triggers the CaMKKβ/AMPK/Beclin1 pathway, initiating autophagy. This intricate interplay between apoptosis and autophagy, instigated by bufalin, culminates in cell death within osteosarcoma (OS).

Store-operated Ca²⁺ (SOC) channels are the primary contributors to the influx of Ca²⁺ that leads to calcium overload in pancreatic acinar cells.²⁷⁷ Activation of SOC channels induces the initiation of a cascade involving the activation of calcineurin (CaN), which, in turn, stimulates activation of the transcription factor EB (TFEB).²⁷⁸ This activation of TFEB has enduring effects on autophagy and vacuolization, notably influencing the development of acute pancreatitis (AP). The mitochondrial calcium uniporter regulator 1 (MCUR1), a 40 kDa protein situated in the IMM, interacts with the MCU.²⁷⁹ Silencing MCUR1 significantly inhibits agonist-induced mitochondrial Ca²⁺ uptake. Notably, MCUR1 depletion precipitates a cellular bioenergetic crisis, triggering the autophagic process. The regulatory role of promyelocytic leukemia protein (PML) extends to the modulation of IP₃R3 activity, governing the autophagic response.²⁸⁰ This modulation is integral to the requirement for efficient Ca²⁺ transfer from the ER to mitochondria, which is essential for meeting cellular energy demands and facilitating mitochondrial metabolism. Diminished IP₃ receptor activity leads to reduced Ca²⁺ transfer which compromises mitochondrial function and ATP generation, ultimately instigating autophagy.

4.1.5 Calcium-triggered other types of cell death. Under conditions of oxidation and autophosphorylation mediated by receptor-interacting protein 3 (RIP3), CaMKII significantly enhances mPTP-dependent necroptotic pathways, demonstrating independence from RIP1 and MLKL.²⁸¹ Ca²⁺ also triggers LDCD by activation of calpains and induction of LMP.²⁸² The Ca-calpain axis also induces LDCD accompanied with apoptosis. Additionally, [Ca²⁺]i triggers the SEPTIN-Orai1-Ca²⁺/CaM-myosin light chain kinase (MLCK)-actomyosin axis to regulate entosis.²⁸³ These insights underscore the need to increase our understanding of intracellular Ca²⁺ interactions for a more refined application of Ca²⁺-based pharmacological agents in PCD.

4.2 Iron-triggered programmed cell death

Iron ions are crucial transition metal ions ubiquitous in living organisms. However, excessive accumulation of iron is regarded as a risk factor for cancer, contributing to both carcinogenesis and the metastasis of cancer cells.²⁸⁴ The principal detrimental effects arising from the induction of free radicals, facilitated by iron ions, are evidenced through the manifestation of diverse DNA oxidation products. The process of lipid peroxidation is intricately associated with the catalytic influence of Fe²⁺ and Fe³⁺, giving rise to alkoxyl radicals (RO·) and peroxyl radicals (ROO·).²⁸⁵ The cyclization of RO· originating from arachidonic acid results in the formation of 4-hydroxynonenal. This molecule has been implicated as a putative causative factor in various diseases, including multiple cancer types. Consequently, the scrutiny of iron-triggered PCD has become a focal point, particularly within the realms of apoptosis, necroptosis, ferroptosis, and pyroptosis (Fig. 10).

Fig. 10 Schematic signaling pathway of representative iron-triggered programmed cell death.

4.2.1 Iron-triggered apoptosis. The overabundance of iron instigates ROS generation, predominantly within mitochondria. This oxidative process is mediated by the peroxidase activity associated with the cardiolipin–cytochrome c complex.²⁸⁶ Sequential to caspase activation, there is an augmentation in mitochondrial ROS production. This amplification is attributed to the caspase-mediated cleavage of p75 NDUFS1, a protein containing Fe–S.²⁸⁷ Following ROS amplification and MOMP, diverse apoptotic signaling pathways and disruptions to organelle are initiated. ASK1 (apoptosis signal-regulating kinase 1) is a pivotal mediator in ROS-dependent apoptosis.²⁸⁸ Activation of the MAPK pathway p38 and c-Jun N-terminal kinase (JNK) culminates in apoptosis. Importantly, iron overload-induced ROS precipitates DNA damage, initiating p53 activation and culminating in MOMP-dependent apoptosis.²⁸⁹ Iron depletion fosters alternative splicing of Fas, leading to an augmented production of the antiapoptotic, soluble Fas variant.²⁹⁰ Conversely, iron overload inhibits Fas alternative splicing, giving rise to the proapoptotic, membrane-binding form of Fas.

4.2.2 Iron-triggered necroptosis. The association between iron and necroptosis is well established given the regulatory influence of iron on Fas and ROS.²⁹¹ Cultured cells undergoing necroptosis exhibit increased mitochondrial ROS generation. The regulatory impact of labile iron levels on necroptosis is discernible in mouse L929 fibrosarcoma.²⁹² Cell surface NOX complexes, featuring iron-containing proteins, interact with TNF receptors, establishing them as the principal contributors to death-inducing ROS during necroptosis.²⁹³ Observations from human Jurkat and other cell types indicate that necroptosis can manifest independently of ROS.¹⁴⁹ This observation invites further exploration into the cell type-specific role that iron and ROS may assume in the execution of cell death during necroptosis. Additionally, the iron-containing biomolecule heme has been identified as a regulator of necroptosis, particularly in macrophages, where it can induce necroptosis through autocrine TNF and ROS production.²⁹⁴ An in-depth exploration of the necroptotic pathway is anticipated to emerge as a central focus in PCD.

4.2.3 Iron-triggered ferroptosis. Iron plays an important role in numerous redox-based metabolic processes associated with the production of cellular ROS.²⁹⁵ Ferroptosis is contingent upon iron and induced by lipid ROS. The inhibition of GPX4 results in the prolonged presence of phospholipid hydroperoxides (PLOOHs), triggering the Fenton reaction and a swift amplification of PLOOHs.²⁹⁶ The reactivity of PLOOHs extends to both ferrous and ferric ions, yielding the PLO˙ and PLOO˙ free radicals, respectively.⁵⁴ This process instigates a deleterious peroxidation chain reaction. Iron is a requisite cofactor for the catalytic activity of LOXs and cytochrome P450 oxidoreductase (POR).²⁹⁷ LOXs can directly initiate ferroptosis by contributing to the cellular pool of PLOOHs. POR contains a heme iron group, further promoting ferroptosis by up-regulating polyunsaturated phospholipids. Deletion of NRF2 leads to the accumulation of apoferritin within autophagosomes, an increased labile iron pool (LIP), and heightened susceptibility to ferroptosis.²⁹⁸ Furthermore, the release of iron through heme degradation has been associated with ferroptosis, such as nuclear receptor coactivator 4 (NCOA4)-dependent ferritin degradation.²⁹⁹ Silencing NCOA4 or autophagy-related genes like ATG5, ATG7, and ATG13 inhibits the degradation of ferritin, thereby suppressing lysosomal iron release and lipid ROS generation.³⁰⁰ Collectively, diverse cellular processes intricately modulate cellular ferroptosis sensitivity by manipulating iron content, accentuating the indispensable role of iron in both direct and indirect lipid ROS formation. Downstream activation of the ASK1-p38 pathway has been recently observed in response to lipid ROS and ferroptosis regulators in the A549 cell line.³⁰¹ Additionally, Yu et al. recently revealed compensatory upregulation of the metal transporter SLC39A14 in hepatocytes lacking transferrin expression, resulting in an influx of iron and consequent ferroptosis induction.³⁰²

4.2.4 Iron-triggered pyroptosis. Iron-induced ROS activation initiates the Tom20-Bax-caspase-GSDM pathway, ultimately instigating pyroptosis.^183,303 Within melanoma cells, the initiation of ROS signaling, activated by iron, occurs through exposure to exogenous iron (FeSO₄) as well as the ROS inducer such as carbonyl cyanide m-chlorophenyl hydrazone (CCCP). Recently, an engineered ferritin-targeting proteolysis targeting chimera (PROTAC) was developed to introduce a pyroptosis inducer for anticancer treatment.³⁰⁴

4.2.5 Iron-triggered other types of cell death. Iron homeostasis is tightly related to lysosomes. Disruption of the lysosomal acidic environment induces LMP and the release of iron, which triggers ferroptosis via an autophagy-dependent manner. In addition, this lysosome-active change increases LMP and LDCD.³⁰⁵ Besides, iron overload triggers endolysosomal deficits through NAADP-regulated 2-pore channels and RAB7A.³⁰⁶ The relationship between iron and autophagy is complex. Iron overload can trigger autophagy. However, it will impair autophagy later.³⁰⁷ Additionally, iron deficiency inhibits autophagy by activation of ER stress response, then induce apoptosis.³⁰⁷ Therefore, enhancing our comprehension of intracellular iron has tremendous potential for leveraging PCD in the treatment and prevention of cancer.

4.3 Copper-triggered programmed cell death

Copper is implicated in the modulation of multiple signaling pathways within tumor cells.³⁰⁸ Emerging evidence underscores copper's role in activating enzymes and signaling cascades associated with metastasis, thereby propagating malignancy.³⁰⁹ Its direct involvement is manifested through the binding and activation of key molecules. Noteworthy is the direct activation of PI3K by copper, instigating downstream AKT activation. Simultaneously, copper interacts with mitogen-activated protein kinase kinase 1 (MEK1), facilitating the phosphorylation of ERK1/2. This, in turn, triggers c-JNK, thereby orchestrating regulatory mechanisms in tumor growth. Consequently, this discussion summarizes recent research advancements elucidating Cu-triggered PCD (Fig. 11).

Fig. 11 Schematic signaling pathway of representative copper-triggered programmed cell death.

4.3.1 Copper-triggered apoptosis. The Fenton reaction stands out as a prevalent pathway for Cu-catalyzed ROS production, culminating in mitochondrial dysfunction and expedited apoptosis.³¹⁰ Excess copper in the liver induces ROS generation and alterations in mitochondrial transmembrane potential, instigating p53-mediated cell intrinsic apoptosis. Yip et al. reported the induction of ROS production by the DSF–Cu²⁺ complex, leading to the activation of downstream apoptosis-related pathways involving JNK and p38MAPK in breast cancer cells.³¹¹ The combination of Cyt C, apoptotic protease-activating factor 1 (Apaf-1), and caspase 9 gives rise to an “apoptosome,” initiating hepatocyte apoptosis. Various chelators, such as 8-hydroxyquinoline,³¹² dithiocarbamate,³¹³ and clioquinol,³¹⁴ can form complexes with copper salts, exhibiting potent proteasome inhibitory effects and inducing apoptosis in cultured human cancer cells. Notably, proteasome inhibition leads to the translocation of Cyt C to the cytoplasm, activating the caspase cascade and promoting apoptosis.³¹⁵ The robust proteasome inhibitory capabilities of copper complexes position them as promising targets for tumor therapy.

4.3.2 Copper-triggered ferroptosis. The intersection of copper metabolism and ferroptosis has been infrequently discussed in the existing literature.³¹⁶ However, a substantive connection between the two emerges, particularly involving the key ferroptosis-associated gene GPX4.²⁷² Specifically, exogenous copper has been shown to facilitate GPX4 ubiquitination by binding to cysteines C107 and C148, leading to increased GPX4 aggregation.²⁷² Additionally, Tax1-binding protein 1 (TAX1BP1) plays a pivotal role in the breakdown of GPX4, leading to lipid peroxide build-up and triggering ferroptosis. Furthermore, DSF/Cu has been identified as an inducer of ferroptosis, exhibiting synergistic effects with sorafenib in combating HCC.³¹⁷ In hepatocytes, the active intracellular iron transport occurs through the plasma ceruloplasmin (CP)-ferroportin transport system.³¹⁸ Overexpression of CP in HCC cells has demonstrated inhibitory effects on ferroptosis triggered by agents like erastin and RSL3. Notably, the copper metabolism MURR1 domain 10 protein plays a pivotal role in regulating radioresistance in HCC.³¹⁹ This regulation involves copper aggregation, CP, and SLC7A11 upregulation.³²⁰ Consequently, this process diminishes lipid peroxidation levels and effectively inhibits ferroptosis.

4.3.3 Copper-triggered cuproptosis. Identified in the 1980s, copper-induced cell death (Cu-ICD) was not fully understood until 2019.³²¹ The discovery of cuproptosis progressed with the exploration of copper ionophores, lipid-soluble molecules that reversibly bind copper ions. Notably, these compounds are now being explored as potential antitumor therapies. Elesclomol (ES) exhibits the capacity to bind with ferredoxin 1 (FDX1), resulting in the inhibition of Fe–S clusters.⁴ Additionally, it can directly interact with mitochondrial membranes, inducing mitochondrial membrane potential polarization. This, in turn, culminates in cell death through a ROS-mediated mechanism. This assertion finds support in the established correlation between Cu-ICD and mitochondrial metabolism. In tumor treatment with ES, FDX1 exhibits noteworthy metalloreductase activity, converting ES–Cu²⁺ to free Cu⁺.¹⁹² The liberated copper enters the mitochondrial copper pool, contributing to the formation of CCO or binding to lipoylated proteins, ultimately inducing cellular cuproptosis.

4.3.4 Copper-triggered autophagy-dependent cell death. Elevated levels of Cu⁺ induce significant ROS production during oxidation, a phenomenon integral to the initiation of autophagy. At the core of autophagy regulation lies ULK1/2, an essential kinase component within the autophagy-specific type III PI3K complex.³²² Activation of ULK1/2, contingent upon copper availability, promotes autophagic flux, with reduced intracellular copper levels correlated with a reduction in autophagy. Moreover, surplus copper has the potential to enhance autophagic flux. This is achieved through the activation of key autophagy-related components, including ATG5 and BECN1,³²³ along with the modulation of AMPK-mTOR pathways.³²⁴ Additionally, copper expedites the formation of autophagic vesicles by influencing the transcription factors TFEB.³²⁵ In human lung adenocarcinoma cells, antioxidant 1 orchestrates the transfer of copper to cysteine-rich protein 2 (CRIP2), inducing ubiquitin-mediated degradation of CRIP2 and leading to an upregulation of ROS, ultimately activating autophagy.³²⁶ These findings unveil novel copper-dependent targets with the potential to impact tumor growth and progression.

4.3.5 Copper-triggered other types of cell death. Copper overload triggers necroptosis. It ions and compounds can selectively regulate necroptosis in cancer cells, such as CuS–MnS₂ nano-flowers.³²⁷ Recently, a copper-bacteriochlorin nanosheet pyroptosis inducer and multifunctional copper–phenolic nanopillars have been designed to active CASP 1 for inducing pyroptosis in cervical and breast cancer, respectively.^328,329 Consequently, the exploration of intracellular copper-dependent targets presents a promising avenue for harnessing PCD.

4.4 Zinc-triggered programmed cell death

Zinc, a robust inhibitor of caspases 3, -7, and -8, intricately regulates caspase-mediated inflammatory cascades.³³⁰ The intricate impact of zinc on tumor growth manifests in both promotion and inhibition with diverse mechanisms operative across various cancer types.³³¹ Specifically, activation of the extracellular ERK and c-JNK pathways by zinc, both integral to tumorigenesis, underscores its significant contributory role. The dysregulation of ZnT has been extensively validated in numerous studies, showcasing its impact on cell proliferation and apoptosis. Concurrently, this dysregulation precipitates changes in multiple signaling pathways, ultimately contributing to the advancement of cancer.³³² The exploration of zinc's pharmacological mechanisms across various PCDs and its prospective application in PCD is an avenue for further research (Fig. 12).

Fig. 12 Schematic signaling pathway of representative zinc-triggered programmed cell death.

4.4.1 Zinc-triggered apoptosis. ZIP10, a zinc importer protein crucial for B cell survival, plays a key role in apoptotic signaling pathways.¹⁰³ Zn²⁺ exerts a dose-dependent inhibitory effect on key mediators of the apoptotic pathway, including caspases-3, -6, and -8. Zn²⁺ emerges as a potent inducer of ROS generation, disrupting mitochondrial functions and inducing cellular apoptosis. Overexpression of ZnT2 in MDA-MB-231 cells has been associated with notable alterations in cellular processes, including shifts in the cell cycle, heightened apoptosis, and diminished proliferation and invasion capabilities.³³³ Furthermore, the aging process correlates with organismal immunological decline, encompassing neuroendocrine functions and an elevation in apoptosis regulated by zinc deficiency. Zinc deficiency was shown to enhance the rate of apoptosis in immature T cells during sepsis.³³⁴ Chelation of zinc demonstrated intensified apoptosis induced by lipopolysaccharide (LPS) in pulmonary endothelial cells, thereby counteracting the protective effects conferred by nitric oxide (NO) donors against LPS-induced apoptosis.³³⁵

4.4.2 Zinc-triggered lysosome-dependent cell death. Within cellular processes, the lysosome assumes a pivotal role as the central degradative unit. MT-3, as a potential source of labile zinc to modulate lysosomal functions, orchestrates cellular dynamics by regulating lysosome-associated membrane proteins, along with specific lysosomal enzymes.³³⁶ The absence of MT-3 precipitates a reduction in autophagic flux. LMP is implicated in cell death processes induced by oxidative stress, p53 activation, Ca overload, and exposure to lysosomotropic toxins. In conditions of oxidative stress in cultured brain cells, escalation of zinc concentration within autophagic vacuoles, inclusive of autolysosomes, is deemed essential for LMP and subsequent cell death. Numerous cancer chemotherapeutic agents have been demonstrated to synergize Zn²⁺ to elicit lysosomal changes, encompassing LMP, across various cancer cell types.^337,338

4.4.3 Zinc-triggered autophagy-dependent cell death. Zn²⁺ wields a pivotal influence over autophagy dynamics, reciprocally influencing intracellular zinc concentrations.^339,340 Activation of nucleotide-binding oligomerization domain-2 (NOD2) precipitates an intracellular zinc surge, subsequently promoting autophagy.³⁴¹ Conversely, zinc deficiency induces cell death by provoking oxidative stress and ROS generation. Consequently, zinc insufficiency exerts a detrimental impact on PCD. The recognized cytoprotective role of zinc in autophagic processes is noteworthy. Oxidative stress in astrocytes triggers p38 activation, instigating mTOR degradation through phosphorylation and consequent autophagy initiation.³³⁶ Zinc accumulation is discerned in both autophagosomes and lysosomes. The induction of autophagic cell death by tamoxifen in luminal BC cells displays common features, zinc accumulation in autophagic vacuoles and LMP.³⁴² However, treatment with the antioxidant N-acetyl-L-cysteine could decrease zinc accumulation and autophagic cell death. Kim et al. substantiated that the zinc ionophore PCI-5002 induced autophagy in tumor cells.³⁴³ Inhibition of proapoptotic genes increased autophagy through radiosensitization of LC cells by PCI-5002.

4.4.4 Zinc-triggered other types of cell death. In breast cancer, zinc oxide nanoparticles (ZnO NPs) effectively trigger necroptosis and suppress autophagy signaling pathways.³⁴⁴ Besides, ZnO NPs suppress ABCC9 to induce ferroptosis.³⁴⁵ ZIP7 plays a key role in ferroptosis by releasing zinc from the ER to the cytosol, further enhancing ferroptosis.³⁴⁶ Zinc overload also triggers pyroptosis. On the contrary, low concentrations of Zn induces apoptosis.³⁴⁷ Zeolitic imidazolate framework-8 has been demonstrated to trigger pyroptosis through pathway of CASP 1/GSDMD.³⁴⁸ Su et al. designed a novel Pt^IV-terthiophene complex to disrupt zinc homeostasis for triggering GSDMD-mediated pyroptosis.³⁴⁹ These findings shed light on zinc homeostasis disruption and its role in cancer progression, offering noteworthy insights into potential therapeutic strategies for PCD.

4.5 Other metal-triggered programmed cell death

Besides these four primary intracellular metals that can trigger different types of PCD in cancers, other intracellular metals (Fig. 13), such as Mn²⁺, Mg²⁺, and Co²⁺, play an important role in inducing cancer cell death by PCD. Briefly, Table 3 highlights metal ions and their related cell death modes in cancer treatments. Mg²⁺ is preferentially permeable to transmembrane cation channels formed by MLKL protein, a key factor in TNF-induced necroptosis.³⁵⁰ Increasing intracellular Mg²⁺ has been demonstrated to induce apoptosis in breast cancers.³⁵¹ Mn²⁺ not only induced neurological apoptosis by enhancing endoplasmic reticulum stress but triggered pyroptosis through ROS-activated caspase-3/GSDME.^116,352 Increasing intracellular Mn²⁺ could also induce apoptosis in cervical cancer.³⁵³ Co^2+/3+ could trigger apoptosis in various cancers by mimicking the hypoxic factor and Co³⁺-ligand to induce ROS, respectively.^354,355 Notably, some of these intracellular metal ions are integral to various types of PCD because they are implicated in different signaling pathways to regulate cell death, a process further complicated by its diverse subroutines and external influences.³⁵⁶ Zn²⁺, Ca²⁺, and Mg²⁺ help stabilize cell membrane integrity by crosslinking with organic “building blocks,” counterbalanced by organic anions. Ca²⁺ plays a unique role in information transmission, influenced by its variable ionic characteristics. Furthermore, metalloenzymes utilize Mg²⁺ and Zn²⁺ for catalytic activity, whereas metal centers such as Fe^2+/3+, Cu^+/2+, Mn^2+/3+/4+, and Co^2+/3+, driven by specific ligand interactions, facilitate electron transfers.

Fig. 13 Schematic signaling pathway of representative other intracellular metal ions-triggered programmed cell death.

Table 3 Representative cell death modes in various tumors triggered by intracellular metal ions

Metal ion		Cell death mode	Key pathways	Tumor type	Ref.
Calcium		Apoptosis	SERCA, RyR, IP3R, BIRD-2, MFN2, CaMKII	Prostate cancer, lung cancer, osteosarcoma	260–264
		Pyroptosis	NLRP3, Caspase 3, CaSR		265–269
		Ferroptosis	ESCRT-III		270–275
		Autophagy-dependent cell death	CaMKKβ/AMPK, mTORC1, SOC, MCUR1		276–280
		Necroptosis	mPTP, RIP1 and MLKL		281
		LDCD	Ca-calpain axis		282
		Entosis	MLCK-actomyosin axis		283
Iron		Apoptosis,	ASK1, Fas;	Renal cell carcinoma, colorectal cancer, lung cancer, melanoma	286–289
		Necroptosis,	STAT3, GRIM-19, NOX;		291–294
		Ferroptosis,	PLOOH, LOX, POR, NCOA4, NRF2, SLC39A14;		295–302
		Pyroptosis,	Tom20-Bax-caspase-GSDM;		303,304
		LDCD	NAADP-regulated 2-pore, RAB7A		305,306
Copper		Apoptosis,	p53, JNK, p38MAPK, Cyt C, Apaf-1, Caspase 9;	Pancreatic cancer, breast cancer, lung cancer	310–315
		Ferroptosis,	GPX4, TAX1BP1, CP;		316–320
		Cuproptosis,	Elesclomol, FDX1;		192,321
		Autophagy-dependent cell death,	ULK1/2, ATG5, BECN1, CRIP2, UBE2D2;		322–326
		Necroptosis,	ROS,		327
		Pyroptosis	CASP 1		328,329
Zinc		Apoptosis,	ZIP10, Caspase 3, Caspase 6, Caspase 8, Zfp260;	Breast cancer, colorectal cancer, gastric cancer	333–335
		LDCD,	MT-3		336–338
		Autophagy-dependent cell death,	ERK, Beclin 1		339–343
		Necroptosis,	ROS		344
		Ferroptosis,	ABCC9		345,346
		Pyroptosis	CASP 1, GSDMD		347–349
Others	Magnesium	Apoptosis	TRPV1, TRPM7	Breast cancer	350,351
	Manganese	Apoptosis,	cGAS, STING	Cervical cancer	116
		Pyroptosis	Caspase 3, GSDME		352,353
	Cobalt	Apoptosis	phosphatidylserine, BAX, BID, BAD, BAK, BCL-2, BCL-xL, MCL-1	Breast cancer, glioblastoma, lung cancer, cervical cancer, colon cancer	354,355

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4.6 Multiple metal ions-triggered programmed cell death

As described previously, the ability of single metal ions to induce multiple forms of PCD, coupled with the observation that various metal ions can activate the same PCD pathways, highlights their complex roles in cancer therapy. Intracellularly, metal ions have been shown to interact synergistically or competitively, thereby affecting each other's capacity to induce PCD and playing a critical role in cancer treatment strategies. Ca²⁺ is a ubiquitous mediator of cell functions, which has been reported to be modulated by several intracellular metal ions; therefore, it is selected as a specific target to trigger PCD strategically. Fe²⁺ disrupts homeostasis of Ca²⁺ by lipid peroxidation, overlapping effects on HIF-1, ROS-mediated activation of IP₃R/RyR channels, and excitotoxicity.³⁵⁷ Cu increases the [Ca²⁺]i to activate the exchange of Na⁺/Ca²⁺ and results non-specific membrane leaks, which further enhances Cu-toxicity to trigger cell death.³⁵⁸ Zn²⁺, as a second messenger, can modulate L-type Ca²⁺ and K⁺ channels.³⁵⁹ ZIP7 releases Zn²⁺ from the ER to the cytosol, leading to mitochondrial Ca²⁺ uptake for dually triggering ferroptosis.³⁴⁶ Jiang et al. also demonstrated that overload Zn²⁺ disrupted [Ca²⁺]i homeostasis, inhibited ETC, and promoted ROS to trigger apoptosis.³⁶⁰ In addition, Mg²⁺ regulates the mitochondrial calcium uniporter (MCU) and mediates mitochondrial Ca²⁺ uptake. Moreover, Ca²⁺ overloading occurs with a decrease of mitochondrial matrix Mg²⁺. However, with the opening of the mPTP, MCU activity has been increased.³⁶¹ Recently, Zn²⁺/Fe²⁺/Mg²⁺-ion-chelated L-phenylalanine nanostructures induce Ca²⁺ influx to trigger the inflammasome pathway by K⁺ efflux, activating the NF-κB pathway and further augmenting immunotherapy.³⁶² Fe and Cu can also interact with each other. For example, Cu always positively influences the transport of Fe. Fe may antagonize Cu metabolism.³⁶³ Additionally, Cu⁺ replaces other metal sites in protein structures, such as disruption of Zn²⁺ binding ligand in zinc-finger DNA and metalloprotein X-linked inhibitor of apoptosis protein (XIAP).^330,364 Intracellular metal ions thus serve multifaceted roles in biological systems, and their dysregulation can lead to different types of PCD.

Modulating intracellular metal ions presents a novel avenue for regulating PCD, as the dyshomeostasis of various metals can positively impact therapeutic outcomes. The successful application of metal-focused strategies in PCD heavily relies on leveraging the overexpression of intracellular metal ions. Intracellular redox-active metals, such as Fe^2+/3+, Cu^+/2+, Mn^2+/3+/4+, and Co^2+/3+, are cytotoxic due to their role in ROS generation. Metal ions such as Ca²⁺, Zn²⁺, and Mg²⁺ are essential cofactors in enzymatic catalysis and cellular metabolism. These distinct properties provide opportunities for tailoring PCD mechanisms, offering new directions for cancer treatment. A deeper understanding of the mechanisms underlying the interaction between intracellular metal ions and PCD is crucial for advancing direct antitumor strategies. Moreover, the induction of PCD by multiple intracellular metal ions highlights the complex interplay among these ions. The observed ability of multiple metal ions to trigger PCD points to intricate inter-ion interactions within cells. This insight advocates a broader focus on modulating intracellular metal ion networks, positioning their regulation as a strategic approach to inducing PCD for cancer treatment.

5 Conclusion: challenges and future directions

The signaling of intracellular metal ions is crucial in maintaining cellular homeostasis and plays a significant role in regulating physiological activity, especially programmed cell death (PCD).³⁶⁵ Understanding the mechanisms of these ion-based chemical reactions is essential for regulating PCD in disease and the advancement of novel treatments.³⁶⁶ As cancer is one of the most severe diseases and can be very challenging to treat, this review is directed towards PCD via metal-based chemistry reactions that ultimately induce the demise of cancer cells.

Intracellular metal ions present significant prospects in biological and biochemical research, yet their application is fraught with challenges. A primary concern is their double-edged sword in cellular processes, which has yielded conflicting clinical outcomes regarding disease development. This underscores the need for more robust clinical trials. Despite significant advances in understanding the mode of action of metal-based chemistry reactions that induce PCD, the relationship between anti-tumor concentration and reactivity remains elusive. In addition, key questions remain unanswered, including the specifics of the death phenotype, the underlying mechanisms of cell destruction, and the potential roles of these ions in subcellular organelles. Moreover, designing metal-based chemistry reactions to target specific cell death pathways is particularly challenging due to the intricate signaling networks involved in cell death modes. The ideal intracellular metal ion concentration varies between organs, which is critical for refining metal ion-based drug therapies. Future developments in intracellular ion regulators should prioritize organ and cell specificity, as well as controlled release mechanisms.

Advancements understanding of diverse PCD types and their complex molecular interrelations have added complexity to the field. This interconnectedness often results in concurrent activation of multiple cell death pathways, rendering molecular markers less distinct in identifying specific types.³⁶⁷ Four key metals—Ca, Fe, Cu, and Zn are frequently reported to induce cancer cell death by triggering distinct PCDs. Other metals, such as Mg, Mn, and Co, also activate PCD in tumors. Inspired by identified ferroptosis, cuproptosis, and the emerging concept of calcicoptosis,¹³ we envision that other metal-based new cell death modes could emerge as targets of cell death pathways for future cancer treatment. What's more, the effectiveness and specificity of intracellular metal ions in modulating these distinct cell death pathways continue to be a significant concern in the field.

Addressing the challenges posed by intracellular metal ion dyshomeostasis and leveraging these ions for PCD necessitates a comprehensive understanding of their role in cancer-related cell death via PCD pathways.³⁶⁸ This understanding is fundamental for evolving new cancer treatment methodologies. Although a series of metal-based chemistry reactions have been reported to induce common PCD, such as apoptosis, ferroptosis, and pyroptosis, some molecular mechanisms of other PCDs that were triggered by intracellular metal ions remain to be explored. For example, it remains unclear whether necroptosis exclusively underlies tumor necrosis in all solid tumors. However, emerging evidence suggests that the impact of necroptosis on tumorigenesis can be either promotive or inhibitory, contingent upon the specific tumor type. Therefore, the factors behind the ability of intracellular metal ions to drive necroptosis demand further in-depth investigations. Integrating metal ion-triggered biochemical reactions with diverse PCD mechanisms can potentially overcome limitations of traditional apoptosis-based cancer treatments, including adaptive drug resistance, high recurrence, and poor targeting in hard-to-treat cancers. Considering the complex interactions among different PCDs, note that a single ion can activate multiple PCDs and that multiple ions can initiate the same PCD. Collectively, a thorough understanding of cell death processes and types is essential to comprehend cellular homeostasis. Future research should adopt an integrated approach to explore various cell death types with different intracellular metal ions, focusing on discovering new patterns and their interrelations.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Conflicts of interest

The authors declare no conflicts of interest.

Acknowledgements

Q. H. acknowledges the start-up package support from the University of Wisconsin-Madison. T. W. was supported by TL1TR002375 within the Institute for Clinical and Translational Research at the University of Wisconsin-Madison, supported by U54TR002373.

References

1. J. C. Ameisen, Science, 1996, 272, 1278–1279.
2. S. Nagata and M. Tanaka, Nat. Rev. Immunol., 2017, 17, 333–340.
3. F. Peng, M. Liao, R. Qin, S. Zhu, C. Peng, L. Fu, Y. Chen and B. Han, Signal Transduction Targeted Ther., 2022, 7, 286.
4. P. Tsvetkov, A. Detappe and K. Cai, et al. , Nat. Chem. Biol., 2019, 15, 681–689.
5. Y. Bai, J. Chen and S. C. Zimmerman, Chem. Soc. Rev., 2018, 47, 1811–1821.
6. I. Vitale, F. Pietrocola and E. Guilbaud, et al. , Cell Death Differ., 2023, 30, 1097–1154.
7. T. Song, G. Yang and H. Zhang, et al. , Nano Today, 2023, 51, 101896.
8. X. Dai, Y. Xie, W. Feng and Y. Chen, Angew. Chem., Int. Ed., 2023, 62, e202309160.
9. W. Xu, J. Qian, G. Hou, T. Wang, J. Wang, Y. Wang, L. Yang, X. Cui and A. Suo, Adv. Funct. Mater., 2022, 32, 2205013.
10. K. Zhang, C. Qi and K. Cai, Adv. Mater., 2023, 35, e2205409.
11. P. Tsvetkov, S. Coy and B. Petrova, et al. , Science, 2022, 375, 1254–1261.
12. Y. Huang, G. Qin, T. Cui, C. Zhao, J. Ren and X. Qu, Nat. Commun., 2023, 14, 4647.
13. M. Zhang, R. Song and Y. Liu, et al. , Chem, 2019, 5, 2171–2182.
14. C. C. Daw, K. Ramachandran and B. T. Enslow, et al. , Cell, 2020, 183, 474–489.
15. Y. Deng, F. Jia, P. Jiang, L. Chen, L. Xing, X. Shen, L. Li and Y. Huang, Biomaterials, 2023, 301, 122293.
16. J. F. Seeler, A. Sharma and N. J. Zaluzec, et al. , Nat. Chem., 2021, 13, 683–691.
17. L. A. Finney and T. V. O’Halloran, Science, 2003, 300, 931–936.
18. K. Jomova, M. Makova, S. Y. Alomar, S. H. Alwasel, E. Nepovimova, K. Kuca, C. J. Rhodes and M. Valko, Chem. – Biol. Interact., 2022, 367, 110173.
19. H. Lin, Y. Chen and J. Shi, Chem. Soc. Rev., 2018, 47, 1938–1958.
20. M. Valko, K. Jomova, C. J. Rhodes, K. Kuca and K. Musilek, Arch. Toxicol., 2016, 90, 1–37.
21. D. E. Clapham, Cell, 1995, 80, 259–268.
22. M. J. Berridge, P. Lipp and M. D. Bootman, Nat. Rev. Mol. Cell Biol., 2000, 1, 11–21.
23. R. Bagur and G. Hajnoczky, Mol. Cell, 2017, 66, 780–788.
24. N. Xu, M. Francis, D. L. Cioffi and T. Stevens, Am. J. Physiol.: Cell Physiol., 2014, 306, C636–C638.
25. A. Bononi, C. Giorgi and S. Patergnani, et al. , Nature, 2017, 546, 549–553.
26. S. Fujii, R. Ushioda and K. Nagata, Proc. Natl. Acad. Sci. U. S. A., 2023, 120, e2216857120.
27. S. Linse and S. Forsén, Adv. Second Messenger Phosphoprotein Res., 1995, 30, 89–151.
28. M. D. Bootman, M. J. Berridge and H. L. Roderick, Curr. Biol., 2002, 12, R563–R565.
29. M. J. Berridge, Physiol. Rev., 2016, 96, 1261–1296.
30. S. Gupta and M. J. Kaplan, Nat. Rev. Nephrol., 2016, 12, 402–413.
31. N. Schauble, S. Lang and M. Jung, et al. , EMBO J., 2012, 31, 3282–3296.
32. S. Luo, P. Baumeister, S. Yang, S. F. Abcouwer and A. S. Lee, J. Biol. Chem., 2003, 278, 37375–37385.
33. M. Obeid, A. Tesniere and F. Ghiringhelli, et al. , Nat. Med., 2007, 13, 54–61.
34. S. Zheng, D. Zhao and G. Hou, et al. , Proc. Natl. Acad. Sci. U. S. A., 2022, 119, e2111380119.
35. T. H. Murphy, A. T. Malouf, A. Sastre, R. L. Schnaar and J. T. Coyle, Brain Res., 1988, 444, 325–332.
36. Y. P. Rong, G. Bultynck and A. S. Aromolaran, et al. , Proc. Natl. Acad. Sci. U. S. A., 2009, 106, 14397–14402.
37. M. Calvo Rodriguez and B. J. Bacskai, Trends Neurosci., 2021, 44, 136–151.
38. X. He, C. Hawkins, L. Lawley, M. Wunderlich, B. Mizukawa, X.-M. Zha, S. Halene and J. Fang, Blood, 2019, 134, 2661.
39. J. C. Goldstein, N. J. Waterhouse, P. Juin, G. I. Evan and D. R. Green, Nat. Cell Biol., 2000, 2, 156–162.
40. C. Zhong, J. Yang and Y. Zhang, et al. , Research, 2023, 6, 0159.
41. M. L. Joiner, O. M. Koval and J. Li, et al. , Nature, 2012, 491, 269–273.
42. H. Zhang, T. Zhu and W. Liu, et al. , J. Mol. Med., 2015, 93, 1033–1043.
43. A. Murao, M. Aziz, H. Wang, M. Brenner and P. Wang, Apoptosis, 2021, 26, 152–162.
44. S. Sen, M. Won, M. S. Levine, Y. Noh, A. C. Sedgwick, J. S. Kim, J. L. Sessler and J. F. Arambula, Chem. Soc. Rev., 2022, 51, 1212–1233.
45. J. Wang and K. Pantopoulos, Biochem. J., 2011, 434, 365–381.
46. U. Rauen, A. Springer, D. Weisheit, F. Petrat, H. G. Korth, H. de Groot and R. Sustmann, ChemBioChem, 2007, 8, 341–352.
47. P. J. Aggett, Clin. Endocrinol. Metab., 1985, 14, 513–543.
48. K. Jomova and M. Valko, Toxicology, 2011, 283, 65–87.
49. S. J. Dixon and B. R. Stockwell, Nat. Chem. Biol., 2014, 10, 9–17.
50. B. D'Autreaux and M. B. Toledano, Nat. Rev. Mol. Cell Biol., 2007, 8, 813–824.
51. S. J. Dixon, K. M. Lemberg and M. R. Lamprecht, et al. , Cell, 2012, 149, 1060–1072.
52. D. Shin, J. Lee, J. H. You, D. Kim and J. L. Roh, Redox Biol., 2020, 30, 101418.
53. I. Poursaitidis, X. Wang and T. Crighton, et al. , Cell Rep., 2017, 18, 2547–2556.
54. M. Conrad and D. A. Pratt, Nat. Chem. Biol., 2019, 15, 1137–1147.
55. B. T. Paul, D. H. Manz, F. M. Torti and S. V. Torti, Expert Rev. Hematol., 2016, 10, 65–79.
56. O. Stehling and R. Lill, Cold Spring Harb Perspect. Biol., 2013, 5, a011312.
57. S. Dalleau, M. Baradat, F. Gueraud and L. Huc, Cell Death Differ., 2013, 20, 1615–1630.
58. H. Kuhn, S. Banthiya and K. van Leyen, Biochim. Biophys. Acta, 2015, 1851, 308–330.
59. L. Vernis, N. El Banna, D. Baille, E. Hatem, A. Heneman and M. E. Huang, Oxid. Med. Cell. Longevity, 2017, 2017, 3647657.
60. M. Gao, P. Monian, N. Quadri, R. Ramasamy and X. Jiang, Mol. Cell, 2015, 59, 298–308.
61. B. R. Stockwell, J. P. Friedmann Angeli and H. Bayir, et al. , Cell, 2017, 171, 273–285.
62. M. Gao and X. Jiang, Curr. Opin. Chem. Biol., 2018, 51, 58–64.
63. M. Conrad, V. E. Kagan, H. Bayir, G. C. Pagnussat, B. Head, M. G. Traber and B. R. Stockwell, Genes Dev., 2018, 32, 602–619.
64. A. M. Battaglia, R. Chirillo, I. Aversa, A. Sacco, F. Costanzo and F. Biamonte, Cells, 2020, 9, 1505.
65. M. Gao, J. Yi, J. Zhu, A. M. Minikes, P. Monian, C. B. Thompson and X. Jiang, Mol. Cell, 2019, 73, 354–363.
66. A. Grubman and A. R. White, Expert Rev. Mol. Med., 2014, 16, e11.
67. B. Halliwell, K. Zhao and M. Whiteman, Free Radical Res., 2000, 33, 819–830.
68. N. M. Garza, A. B. Swaminathan, K. P. Maremanda, M. Zulkifli and V. M. Gohil, Trends Endocrinol. Metab., 2023, 34, 21–33.
69. M. Ralle, D. Huster and S. Vogt, et al. , J. Biol. Chem., 2010, 285, 30875–30883.
70. I. F. Scheiber, J. F. B. Mercer and R. Dringen, Prog. Neurobiol., 2014, 116, 33–57.
71. L. Chen, J. Min and F. Wang, Signal Transduction Targeted Ther., 2022, 7, 378.
72. N. Husain and R. Mahmood, Environ. Sci. Pollut. Res., 2019, 26, 20654–20668.
73. B. Blades, S. Ayton, Y. H. Hung, A. I. Bush and S. La Fontaine, Biochim. Biophys. Acta, Gen. Subj., 2021, 1865, 129979.
74. J. Chen, C. Lan and H. An, et al. , Sci. Total Environ, 2021, 760, 143375.
75. M. H. Alqarni, M. M. Muharram, S. M. Alshahrani and N. E. Labrou, Int. J. Biol. Macromol., 2019, 128, 493–498.
76. L. M. Ruiz, A. Libedinsky and A. A. Elorza, Front. Mol. Biosci., 2021, 8, 711227.
77. N. Girerd, J. Intern. Med., 2022, 291, 710–712.
78. B. E. Kim, T. Nevitt and D. J. Thiele, Nat. Chem. Biol., 2008, 4, 176–185.
79. S. Puig and D. J. Thiele, Curr. Opin. Chem. Biol., 2002, 6, 171–180.
80. E. Nyvltova, J. V. Dietz, J. Seravalli, O. Khalimonchuk and A. Barrientos, Nat. Commun., 2022, 13, 3615.
81. J. Bertinato and M. R. L'Abbe, J. Biol. Chem., 2003, 278, 35071–35078.
82. T. D. Rae, P. J. Schmidt, R. A. Pufahl, V. C. Culotta and T. V. O’Halloran, Science, 1999, 284, 805–808.
83. L. Miao and D. K. St. Clair, Free Radical Biol. Med., 2009, 47, 344–356.
84. S. R. Powell, D. Hall and A. Shih, Circ. Res., 1991, 69, 881–885.
85. X. Chen, Q. Cai and R. Liang, et al. , Cell Death Dis., 2023, 14, 105.
86. B. T. Worrell, J. A. Malik and V. V. Fokin, Science, 2013, 340, 457–460.
87. J. Clavadetscher, S. Hoffmann, A. Lilienkampf, L. Mackay, R. M. Yusop, S. A. Rider, J. J. Mullins and M. Bradley, Angew. Chem., Int. Ed., 2016, 55, 15662–15666.
88. M. Yang, Y. Yang and P. R. Chen, Top. Curr. Chem., 2016, 374, 2.
89. Y. You, Q. Deng, Y. Wang, Y. Sang, G. Li, F. Pu, J. Ren and X. Qu, Nat. Commun., 2022, 13, 1459.
90. J. E. Hein and V. V. Fokin, Chem. Soc. Rev., 2010, 39, 1302–1315.
91. Y. You, H. Liu, J. Zhu, Y. Wang, F. Pu, J. Ren and X. Qu, Chem. Sci., 2022, 13, 7829–7836.
92. X. Xue, C. Qian and Q. Tao, et al. , Natl. Sci. Rev., 2020, 8, nwaa286.
93. J. Zhu, Y. You, W. Zhang, F. Pu, J. Ren and X. Qu, J. Am. Chem. Soc., 2023, 145, 1955–1963.
94. C. E. Outten and T. V. O’Halloran, Science, 2001, 292, 2488–2492.
95. T. Hara, T. A. Takeda, T. Takagishi, K. Fukue, T. Kambe and T. Fukada, J. Physiol. Sci., 2017, 67, 283–301.
96. L. Huang and J. Gitschier, Nat. Genet., 1997, 17, 292–297.
97. L. Guo, L. A. Lichten, M. S. Ryu, J. P. Liuzzi, F. Wang and R. J. Cousins, Proc. Natl. Acad. Sci. U. S. A., 2010, 107, 2818–2823.
98. S. Choi, X. Liu and Z. Pan, Acta Pharmacol. Sin., 2018, 39, 1120–1132.
99. Y. Y. Chen and T. V. O’Halloran, Cell, 2022, 185, 2013–2015.
100. A. Krezel and W. Maret, Chem. Rev., 2021, 121, 14594–14648.
101. H. Ma, L. Su, H. Yue, X. Yin, J. Zhao, S. Zhang, H. Kung, Z. Xu and J. Miao, Sci. Rep., 2015, 5, 15121.
102. W. Ohashi, S. Kimura and T. Iwanaga, et al. , PLoS Genet., 2016, 12, e1006349.
103. T. Miyai, S. Hojyo and T. Ikawa, et al. , Proc. Natl. Acad. Sci. U. S. A., 2014, 111, 11780–11785.
104. D. Liang, L. Xiang, M. Yang, X. Zhang, B. Guo, Y. Chen, L. Yang and J. Cao, Cell. Signalling, 2013, 25, 1126–1135.
105. P. Thomas, Y. Pang, J. Dong and A. H. Berg, Endocrinology, 2014, 155, 4250–4265.
106. J. Sterling, S. Guttha, Y. Song, D. Song, M. Hadziahmetovic and J. L. Dunaief, Exp. Eye Res., 2017, 155, 15–23.
107. O. Florey, S. E. Kim, C. P. Sandoval, C. M. Haynes and M. Overholtzer, Nat. Cell Biol., 2011, 13, 1335–1343.
108. S. Krishna, W. Palm, Y. Lee, W. Yang, U. Bandyopadhyay, H. Xu, O. Florey, C. B. Thompson and M. Overholtzer, Dev. Cell, 2016, 38, 536–547.
109. Y. Zhang, E. Aizenman, D. B. DeFranco and P. A. Rosenberg, Mol. Med., 2007, 13, 350–355.
110. I. Kim, E. J. Park, J. Seo, S. J. Ko, J. Lee and C. H. Kim, NeuroReport, 2011, 22, 839–844.
111. X. Y. Sun, Y. P. Wei and Y. Xiong, et al. , J. Biol. Chem., 2012, 287, 11174–11182.
112. Q. Sun, W. Zhong, W. Zhang, Q. Li, X. Sun, X. Tan, X. Sun, D. Dong and Z. Zhou, Am. J. Physiol.: Gastrointest. Liver Physiol., 2015, 308, G757–G766.
113. K. Homma, T. Fujisawa and N. Tsuburaya, et al. , Mol. Cell, 2013, 52, 75–86.
114. R. A. Yokel, J. Alzheimer's Dis., 2006, 10, 223–253.
115. R. H. Kretsinger., V. N. Uversky and E. A. Permyakov, Encyclopedia of Metalloproteins, 2013.
116. C. Wang, Y. Guan and M. Lv, et al. , Immunity, 2018, 48, 675–687.
117. D. Osman, A. W. Foster, J. Chen, K. Svedaite, J. W. Steed, E. Lurie Luke, T. G. Huggins and N. J. Robinson, Nat. Commun., 2017, 8, 1884.
118. W. Yang, J. Y. Lee and M. Nowotny, Mol. Cell, 2006, 22, 5–13.
119. F. Y. Li, B. Chaigne-Delalande and C. Kanellopoulou, et al. , Nature, 2011, 475, 471–476.
120. T. E. Gunter, C. E. Gavin, M. Aschner and K. K. Gunter, Neurotoxicology, 2006, 27, 765–776.
121. J. Lee, D. A. Kitchaev and D. H. Kwon, et al. , Nature, 2018, 556, 185–190.
122. K. J. Waldron, J. C. Rutherford, D. Ford and N. J. Robinson, Nature, 2009, 460, 823–830.
123. M. Giedyk and D. Gryko, Chem. Catal., 2022, 2, 1534–1548.
124. R. Ortega, C. Bresson and A. Fraysse, et al. , Toxicol. Lett., 2009, 188, 26–32.
125. A. B. Moshnikova, S. A. Moshnikov, V. N. Afanasyev, K. E. Krotova, V. B. Sadovnikov and I. P. Beletsky, Int. J. Biochem. Cell Biol., 2001, 33, 1160–1171.
126. B. A. Carneiro and W. S. El-Deiry, Nat. Rev. Clin. Oncol., 2020, 17, 395–417.
127. R. Valentin, S. Grabow and M. S. Davids, Blood, 2018, 132, 1248–1264.
128. A. Jain, J. Gosling and S. Liu, et al. , Nat. Nanotechnol., 2024, 19, 106–114.
129. E. C. Josefsson, D. L. Burnett and M. Lebois, et al. , Nat. Commun., 2014, 5, 3455.
130. T. Xu, Q. Ma and Y. Li, et al. , Signal Transduction Targeted Ther., 2022, 7, 354.
131. X. Huang, Z. Cao and J. Qian, et al. , Nat. Nanotechnol., 2024, 19, 545–553.
132. W. Zhang, Z. Liu, J. Zhu, Z. Liu, Y. Zhang, G. Qin, J. Ren and X. Qu, J. Am. Chem. Soc., 2023, 145, 16658–16668.
133. B. Z. Carter, W. Tao and L. B. Ostermann, et al. , Blood, 2021, 138, 3332.
134. S. T. Diepstraten, M. A. Anderson, P. E. Czabotar, G. Lessene, A. Strasser and G. L. Kelly, Nat. Rev. Cancer, 2021, 22, 45–64.
135. E. A. Bowling, J. H. Wang and F. Gong, et al. , Cell, 2021, 184, 384–403.
136. J. Hou, R. Zhao and W. Xia, et al. , Nat. Cell Biol., 2020, 22, 1264–1275.
137. K. A. Sarosiek and K. C. Wood, Trends Cancer, 2023, 9, 96–110.
138. Y. Ge, S. Wu, Z. Zhang, X. Li, F. Li, S. Yan, H. Liu, J. Huang and Y. Zhao, Protein Cell, 2019, 10, 808–824.
139. J. A. Malla, R. M. Umesh, S. Yousf, S. Mane, S. Sharma, M. Lahiri and P. Talukdar, Angew. Chem., Int. Ed., 2020, 59, 7944–7952.
140. J. J. McGuire, J. S. Frieling, C. H. Lo, T. Li, A. Muhammad, H. R. Lawrence, N. J. Lawrence, L. M. Cook and C. C. Lynch, Nat. Commun., 2021, 12, 723.
141. Y. Boege, M. Malehmir and M. E. Healy, et al. , Cancer Cell, 2017, 32, 342–359.
142. G. Liccardi, L. Ramos Garcia and T. Tenev, et al. , Mol. Cell, 2019, 73, 413–428.
143. G. Ichim and S. W. Tait, Nat. Rev. Cancer, 2016, 16, 539–548.
144. J. R. Tejedor, P. Papasaikas and J. Valcarcel, Mol. Cell, 2015, 57, 23–38.
145. J. Yuan, P. Amin and D. Ofengeim, Nat. Rev. Neurosci., 2019, 20, 19–33.
146. D. Bertheloot, E. Latz and B. S. Franklin, Cell. Mol. Immunol., 2021, 18, 1106–1121.
147. Y. S. Cho, S. Challa, D. Moquin, R. Genga, T. D. Ray, M. Guildford and F. K. Chan, Cell, 2009, 137, 1112–1123.
148. E. W. Lee, J. H. Kim and Y. H. Ahn, et al. , Nat. Commun., 2012, 3, 978.
149. A. Degterev, Z. Huang and M. Boyce, et al. , Nat. Chem. Biol., 2005, 1, 112–119.
150. J. Yan, P. Wan, S. Choksi and Z. G. Liu, Trends Cancer, 2022, 8, 21–27.
151. D. Jiao, Z. Cai and S. Choksi, et al. , Cell Res., 2018, 28, 868–870.
152. R. J. Thapa, S. Nogusa, P. Chen, J. L. Maki, A. Lerro, M. Andrake, G. F. Rall, A. Degterev and S. Balachandran, Proc. Natl. Acad. Sci. U. S. A., 2013, 110, E3109–E3118.
153. N. Robinson, S. McComb, R. Mulligan, R. Dudani, L. Krishnan and S. Sad, Nat. Immunol., 2012, 13, 954–962.
154. R. Thijssen, S. Alvarez-Diaz, C. Grace, M.-Y. Gao, D. H. Segal, Z. Xu, A. Strasser and D. C. S. Huang, Cell Death Differ., 2020, 27, 2531–2533.
155. U. Höckendorf, M. Yabal and T. Herold, et al. , Cancer Cell, 2016, 30, 75–91.
156. W. S. Yang, R. SriRamaratnam and M. E. Welsch, et al. , Cell, 2014, 156, 317–331.
157. J. P. Friedmann Angeli, M. Schneider and B. Proneth, et al. , Nat. Cell Biol., 2014, 16, 1180–1191.
158. M. J. Hangauer, V. S. Viswanathan and M. J. Ryan, et al. , Nature, 2017, 551, 247–250.
159. X. Jiang, B. R. Stockwell and M. Conrad, Nat. Rev. Mol. Cell Biol., 2021, 22, 266–282.
160. N. Kang, S. Son, S. Min, H. Hong, C. Kim, J. An, J. S. Kim and H. Kang, Chem. Soc. Rev., 2023, 52, 3955–3972.
161. W. S. Yang, K. J. Kim, M. M. Gaschler, M. Patel, M. S. Shchepinov and B. R. Stockwell, Proc. Natl. Acad. Sci. U. S. A., 2016, 113, E4966–E4975.
162. W. Wang, M. Green and J. E. Choi, et al. , Nature, 2019, 569, 270–274.
163. B. Chu, N. Kon, D. Chen, T. Li, T. Liu, L. Jiang, S. Song, O. Tavana and W. Gu, Nat. Cell Biol., 2019, 21, 579–591.
164. S. Doll, B. Proneth and Y. Y. Tyurina, et al. , Nat. Chem. Biol., 2017, 13, 91–98.
165. T. J. Nevalainen, Virchows Arch. B Cell Pathol., 1975, 18, 119–127.
166. D. Denton and S. Kumar, Cell Death Differ., 2019, 26, 605–616.
167. Z. Zhang and M. Costa, Semin. Cancer Biol., 2021, 76, 267–278.
168. J. Kim, M. Kundu, B. Viollet and K. L. Guan, Nat. Cell Biol., 2011, 13, 132–141.
169. M. C. Maiuri, L. Galluzzi, E. Morselli, O. Kepp, S. A. Malik and G. Kroemer, Curr. Opin. Chem. Biol., 2010, 22, 181–185.
170. H. Zuo, C. Chen and Y. Sa, Pharmacol. Rep., 2023, 75, 499–510.
171. M. Zachari and I. G. Ganley, Essays Biochem., 2017, 61, 585–596.
172. D. F. Egan, M. G. H. Chun and M. Vamos, et al. , Mol. Cell, 2015, 59, 285–297.
173. M. A. Brennan and B. T. Cookson, Trends Microbiol., 2001, 9, 113–114.
174. S. K. Hsu, C. Y. Li and I. L. Lin, et al. , Theranostics, 2021, 11, 8813–8835.
175. N. Kayagaki, I. B. Stowe and B. L. Lee, et al. , Nature, 2015, 526, 666–671.
176. T. D. Kanneganti, M. Lamkanfi and G. Nunez, Immunity, 2007, 27, 549–559.
177. G. P. Amarante-Mendes, S. Adjemian, L. M. Branco, L. C. Zanetti, R. Weinlich and K. R. Bortoluci, Front. Immunol., 2018, 9, 2379.
178. J. Shi, Y. Zhao and K. Wang, et al. , Nature, 2015, 526, 660–665.
179. N. M. de Vasconcelos, N. Van Opdenbosch, H. Van Gorp, E. Parthoens and M. Lamkanfi, Cell Death Differ., 2019, 26, 146–161.
180. A. Al Mamun, A. A. Mimi, M. A. Aziz, M. Zaeem, T. Ahmed, F. Munir and J. Xiao, Eur. J. Pharmacol., 2021, 910, 174444.
181. X. Zhu and S. Li, Adv. Sci., 2023, 10, 2300824.
182. Z. Zheng and G. Li, Int. J. Mol. Sci., 2020, 21, 1456.
183. Y. Wang, W. Gao, X. Shi, J. Ding, W. Liu, H. He, K. Wang and F. Shao, Nature, 2017, 547, 99–103.
184. P. Yu, H. Y. Wang, M. Tian, A. X. Li, X. S. Chen, X. L. Wang, Y. Zhang and Y. Cheng, Acta Pharmacol. Sin., 2019, 40, 1237–1244.
185. J. Yu, S. Li, J. Qi, Z. Chen, Y. Wu, J. Guo, K. Wang, X. Sun and J. Zheng, Cell Death Dis., 2019, 10, 193.
186. C. C. Zhang, C. G. Li and Y. F. Wang, et al. , Apoptosis, 2019, 24, 312–325.
187. J. Xie, Y. Yang, Y. Gao and J. He, Mol. Cancer, 2023, 22, 46.
188. D. Tang, G. Kroemer and R. Kang, Nat. Rev. Clin. Oncol., 2024, 21, 370–388.
189. P. Pei, Y. Wang and W. Shen, et al. , Aggregate, 2024, e484.
190. X. Lun, J. C. Wells and N. Grinshtein, et al. , Clin. Cancer Res., 2016, 22, 3860–3875.
191. M. Zulkifli, A. N. Spelbring and Y. Zhang, et al. , Proc. Natl. Acad. Sci. U. S. A., 2023, 120, e2216722120.
192. M. Buccarelli, Q. G. D’Alessandris and P. Matarrese, et al. , J. Exp. Clin. Cancer Res., 2021, 40, 228.
193. F. Paredes, K. Sheldon and B. Lassegue, et al. , Proc. Natl. Acad. Sci. U. S. A., 2018, 115, 1789–1794.
194. E. A. Rowland, C. K. Snowden and I. M. Cristea, Curr. Opin. Chem. Biol., 2018, 42, 76–85.
195. M. Overholtzer, A. A. Mailleux, G. Mouneimne, G. Normand, S. J. Schnitt, R. W. King, E. S. Cibas and J. S. Brugge, Cell, 2007, 131, 966–979.
196. Q. Sun, E. S. Cibas, H. Huang, L. Hodgson and M. Overholtzer, Cell Res., 2014, 24, 1288–1298.
197. P. A. Kreuzaler, A. D. Staniszewska and W. Li, et al. , Nat. Cell Biol., 2011, 13, 303–309.
198. T. J. Sargeant, B. Lloyd-Lewis, H. K. Resemann, A. Ramos-Montoya, J. Skepper and C. J. Watson, Nat. Cell Biol., 2014, 16, 1057–1068.
199. M. A. Sanjuan, C. P. Dillon and S. W. Tait, et al. , Nature, 2007, 450, 1253–1257.
200. S. E. Kim and M. Overholtzer, Semin. Cancer Biol., 2013, 23, 329–336.
201. X. Wang, Y. Li and J. Li, et al. , Front. Cell Dev. Biol., 2019, 7, 311.
202. J. Song, R. Xu, H. Zhang, X. Xue, R. Ruze, Y. Chen, X. Yin, C. Wang and Y. Zhao, Gastroenterology, 2023, 165, 1505–1521.
203. M. Krajcovic and M. Overholtzer, Cancer Res., 2012, 72, 1596–1601.
204. V. Brinkmann, U. Reichard, C. Goosmann, B. Fauler, Y. Uhlemann, D. S. Weiss, Y. Weinrauch and A. Zychlinsky, Science, 2004, 303, 1532–1535.
205. H. R. Thiam, S. L. Wong, D. D. Wagner and C. M. Waterman, Annu. Rev. Cell Dev. Biol., 2020, 36, 191–218.
206. D. Azzouz, M. A. Khan and N. Palaniyar, Cell Death Discovery, 2021, 7, 113.
207. P. Li, M. Li, M. R. Lindberg, M. J. Kennett, N. Xiong and Y. Wang, J. Exp. Med., 2010, 207, 1853–1862.
208. M. Su, C. Chen and S. Li, et al. , Nat. Cardiovasc. Res., 2022, 1, 732–747.
209. K. W. Chen, M. Monteleone and D. Boucher, et al. , Sci. Immunol., 2018, 3, eaar6676.
210. V. Poli and I. Zanoni, Trends Microbiol., 2023, 31, 280–293.
211. M. Demers, D. S. Krause, D. Schatzberg, K. Martinod, J. R. Voorhees, T. A. Fuchs, D. T. Scadden and D. D. Wagner, Proc. Natl. Acad. Sci. U. S. A., 2012, 109, 13076–13081.
212. S. Sangaletti, C. Tripodo and C. Vitali, et al. , Cancer Discovery, 2014, 4, 110–129.
213. K. K. David, S. A. Andrabi, T. M. Dawson and V. L. Dawson, Front. Biosci., 2009, 14, 1116–1128.
214. S. A. Andrabi, H. C. Kang and J. F. Haince, et al. , Nat. Med., 2011, 17, 692–699.
215. M. Mashimo, J. Kato and J. Moss, Proc. Natl. Acad. Sci. U. S. A., 2013, 110, 18964–18969.
216. Y. Wang, R. An and G. K. Umanah, et al. , Science, 2016, 354, aad6872.
217. Y. Zhou, L. Liu, S. Tao, Y. Yao, Y. Wang, Q. Wei, A. Shao and Y. Deng, Pharmacol. Res., 2021, 163, 105299.
218. S. A. Andrabi, T. M. Dawson and V. L. Dawson, Ann. N. Y. Acad. Sci., 2008, 1147, 233–241.
219. P. Donizy, A. Halon, P. Surowiak, G. Pietrzyk, C. Kozyra and R. Matkowski, Eur. J. Histochem., 2013, 57, e35.
220. N. Pillay, A. Tighe and L. Nelson, et al. , Cancer Cell, 2019, 35, 519–533.
221. D. Li, Y. Kou, Y. Gao, S. Liu, P. Yang, T. Hasegawa, R. Su, J. Guo and M. Li, Aging, 2021, 3, 4242–4257.
222. J. Q. Wang, Y. Tang, Q. S. Li, M. Xiao, M. Li, Y. T. Sheng, Y. Yang and Y. L. Wang, Oncol. Rep., 2019, 41, 2657–2666.
223. U. A. Matulonis, P. Harter and C. Gourley, et al. , Cancer, 2016, 122, 1844–1852.
224. P. Li, Y. Du, J. Qiu, D. Li, G. Li and G. Shan, Adv. Healthcare Mater., 2023, 12, e2301517.
225. M. R. Mirza, B. J. Monk and J. Herrstedt, et al. , N. Engl. J. Med., 2016, 375, 2154–2164.
226. J. K. Litton, H. S. Rugo and J. Ettl, et al. , N. Engl. J. Med., 2018, 379, 753–763.
227. H. Rugo, E. Shtivelman and A. Perez, et al. , Breast Cancer Res. Treat., 2007, 105, 17–28.
228. A. A. Fatokun, V. L. Dawson and T. M. Dawson, Br. J. Pharmacol., 2014, 171, 2000–2016.
229. H. Nakamura, T. Tanaka, C. Zheng, S. A. Afione, B. M. Warner, M. Noguchi, T. Atsumi and J. A. Chiorini, Arthritis Rheumatol., 2023, 75, 1586–1598.
230. G. Kroemer and M. Jaattela, Nat. Rev. Cancer, 2005, 5, 886–897.
231. Z. Zuo, H. Yin, Y. Zhang, C. Xie and Q. Wang, Nat. Commun., 2023, 14, 5456.
232. P. Phadatare and J. Debnath, J. Clin. Invest., 2023, 133, e169240.
233. T. Kurz, A. Terman, B. Gustafsson and U. T. Brunk, Histochem. Cell Biol., 2008, 129, 389–406.
234. A. Sumoza-Toledo and R. Penner, J. Physiol., 2011, 589, 1515–1525.
235. J. Brojatsch, H. Lima, Jr., D. Palliser, L. S. Jacobson, S. M. Muehlbauer, R. Furtado, D. L. Goldman, M. P. Lisanti and K. Chandran, Cell Cycle, 2015, 14, 964–972.
236. K. F. Hsu, C. L. Wu, S. C. Huang, C. M. Wu, J. R. Hsiao, Y. T. Yo, Y. H. Chen, A. L. Shiau and C. Y. Chou, Autophagy, 2009, 5, 451–460.
237. M. Tang, B. Chen and H. Xia, et al. , Nat. Commun., 2023, 14, 5888.
238. M. E. Guicciardi, M. Leist and G. J. Gores, Oncogene, 2004, 23, 2881–2890.
239. M. Mauthe, I. Orhon and C. Rocchi, et al. , Autophagy, 2018, 14, 1435–1455.
240. H. Du Rietz, H. Hedlund, S. Wilhelmson, P. Nordenfelt and A. Wittrup, Nat. Commun., 2020, 11, 1809.
241. F. Chen, R. Kang, J. Liu and D. Tang, Front. Cell Dev. Biol., 2023, 11, 1213995.
242. X. Song, S. Zhu and Y. Xie, et al. , Gastroenterology, 2018, 154, 1480–1493.
243. D. Tang, R. Kang, T. V. Berghe, P. Vandenabeele and G. Kroemer, Cell Res., 2019, 29, 347–364.
244. J. Liu, F. Kuang, R. Kang and D. Tang, Cancer Gene Ther., 2020, 27, 267–269.
245. X. Chen, H. J. Zeh, R. Kang, G. Kroemer and D. Tang, Nat. Rev. Gastroenterol. Hepatol., 2021, 18, 804–823.
246. C. Holze, C. Michaudel and C. Mackowiak, et al. , Nat. Immunol., 2018, 19, 130–140.
247. P. Kang, J. Chen and W. Zhang, et al. , Cell Death Discovery, 2022, 8, 70.
248. S. Pallichankandy, F. Thayyullathil and A. R. Cheratta, et al. , Cell Death Discovery, 2023, 9, 94.
249. B. Pan, B. Zheng, C. Xing and J. Liu, Cancers, 2022, 14, 3309.
250. Y. Zou, J. Xie and S. Zheng, et al. , Int. J. Surg., 2022, 107, 106936.
251. J. Zhang, R. F. Gao, J. Li, K. D. Yu and K. X. Bi, Biochem. Cell Biol., 2022, 100, 213–222.
252. H. Hu, Q. Xu, Z. Mo, X. Hu, Q. He, Z. Zhang and Z. Xu, J. Nanobiotechnol., 2022, 20, 457.
253. Q. Li, Y. Feng, R. Wang, R. Liu, Y. Ba and H. Huang, Toxicol. Res., 2023, 39, 355–372.
254. Y. Luo, Y. Fu, Z. Huang and M. Li, J. Cell. Physiol., 2021, 236, 7144–7158.
255. Y. Guo, Q. Bao, P. Hu and J. Shi, Nat. Commun., 2023, 14, 7306.
256. R. Zimmermann, J. Clin. Immunol., 2016, 36, 5–11.
257. P. Yu, X. Cai, Y. Liang, M. Wang and W. Yang, Molecules, 2020, 25, 4826.
258. Y. D. Zheng, Z. He, Z. C. Su, H. Wang, X. H. Jiang, X. Fang, S. L. Lu and Y. Li, Cell Biol. Int., 2023, 47, 1344–1353.
259. S. Orrenius, B. Zhivotovsky and P. Nicotera, Nat. Rev. Mol. Cell Biol., 2003, 4, 552–565.
260. S. Kuchay, C. Giorgi and D. Simoneschi, et al. , Nature, 2017, 546, 554–558.
261. O. M. de Brito and L. Scorrano, Nature, 2008, 456, 605–610.
262. T. Vervliet, I. Pintelon and K. Welkenhuyzen, et al. , Biochem. Pharmacol., 2017, 132, 133–142.
263. H. Akl, G. Monaco and R. La Rovere, et al. , Cell Death Dis., 2013, 4, e632.
264. M. Kerkhofs, R. La Rovere, K. Welkenhuysen, A. Janssens, P. Vandenberghe, M. Madesh, J. B. Parys and G. Bultynck, Cell Calcium, 2021, 94, 102333.
265. B. Zhou, Y. Lin, S. Chen, J. Cai, Z. Luo, S. Yu and J. Lu, Bull. Exp. Biol. Med., 2021, 171, 297–304.
266. E. M. Brown, G. Gamba and D. Riccardi, et al. , Nature, 1993, 366, 575–580.
267. J. Wang, R. Zhang and Y. Huo, et al. , Ecotoxicol. Environ. Saf., 2019, 175, 251–262.
268. Y. Zhu, G. Xu, P. Chen, K. Liu, Y. Xu, Y. Liu and J. Liu, Ecotoxicol. Environ. Saf., 2019, 179, 257–264.
269. Q. Zhong, T. I. Roumeliotis, Z. Kozik, M. Cepeda-Molero, L. A. Fernandez, A. R. Shenoy, C. Bakal, G. Frankel and J. S. Choudhary, PLoS Biol., 2020, 18, e3000986.
270. P. Maher, K. van Leyen, P. N. Dey, B. Honrath, A. Dolga and A. Methner, Cell Calcium, 2018, 70, 47–55.
271. L. Pedrera, U. Ros and A. J. Garcia-Saez, Cell Calcium, 2023, 114, 102778.
272. Q. Xue, D. Yan and X. Chen, et al. , Autophagy, 2023, 19, 1982–1996.
273. E. Dai, L. Meng, R. Kang, X. Wang and D. Tang, Biochem. Biophys. Res. Commun., 2020, 522, 415–421.
274. L. Pedrera, R. A. Espiritu, U. Ros, J. Weber, A. Schmitt, J. Stroh, S. Hailfinger, S. von Karstedt and A. J. Garcia-Saez, Cell Death Differ., 2021, 28, 1644–1657.
275. J. Zhao, Y. Wu and K. Zhou, et al. , Biochim. Biophys. Acta, Mol. Cell Res., 2023, 1870, 119452.
276. A. Woods, K. Dickerson, R. Heath, S. P. Hong, M. Momcilovic, S. R. Johnstone, M. Carlson and D. Carling, Cell Metab., 2005, 2, 21–33.
277. Z. D. Zhu, T. Yu, H. J. Liu, J. Jin and J. He, Cell Death Dis., 2018, 9, 50.
278. Y. Tong and F. Song, Autophagy, 2015, 11, 1192–1195.
279. K. Mallilankaraman, C. Cardenas and P. J. Doonan, et al. , Nat. Cell Biol., 2012, 14, 1336–1343.
280. S. Missiroli, M. Bonora and S. Patergnani, et al. , Cell Rep., 2016, 16, 2415–2427.
281. T. Zhang, Y. Zhang and M. Cui, et al. , Nat. Med., 2016, 22, 175–182.
282. M. Milani, P. Pihan and C. Hetz, Cell Calcium, 2023, 113, 102751.
283. A. R. Lee and C. Y. Park, Adv. Sci., 2023, 10, e2205913.
284. L. Lin, S. Wang and H. Deng, et al. , J. Am. Chem. Soc., 2020, 142, 15320–15330.
285. G. Spiteller, Free Radical Biol. Med., 2006, 41, 362–387.
286. V. E. Kagan, V. A. Tyurin and J. Jiang, et al. , Nat. Chem. Biol., 2005, 1, 223–232.
287. J. E. Ricci, C. Munoz-Pinedo, P. Fitzgerald, B. Bailly-Maitre, G. A. Perkins, N. Yadava, I. E. Scheffler, M. H. Ellisman and D. R. Green, Cell, 2004, 117, 773–786.
288. H. Ichijo, E. Nishida and K. Irie, et al. , Science, 1997, 275, 90–94.
289. M. Ahamed, M. J. Akhtar, M. A. Siddiqui, J. Ahmad, J. Musarrat, A. A. Al-Khedhairy, M. S. AlSalhi and S. A. Alrokayan, Toxicology, 2011, 283, 101–108.
290. J. Cheng, T. Zhou, C. Liu, J. P. Shapiro, M. J. Brauer, M. C. Kiefer, P. J. Barr and J. D. Mountz, Science, 1994, 263, 1759–1762.
291. T. Vanden Berghe, A. Linkermann, S. Jouan-Lanhouet, H. Walczak and P. Vandenabeele, Nat. Rev. Mol. Cell Biol., 2014, 15, 135–147.
292. C. Xie, N. Zhang, H. Zhou, J. Li, Q. Li, T. Zarubin, S. C. Lin and J. Han, Mol. Cell. Biol., 2005, 25, 6673–6681.
293. Y. S. Kim, M. J. Morgan, S. Choksi and Z. G. Liu, Mol. Cell, 2007, 26, 675–687.
294. G. B. Fortes, L. S. Alves and R. de Oliveira, et al. , Blood, 2012, 119, 2368–2375.
295. J. Zhu, Y. Xiong, Y. Zhang, J. Wen, N. Cai, K. Cheng, H. Liang and W. Zhang, Oxid. Med. Cell. Longevity, 2020, 2020, 8810785.
296. F. Ursini, M. Maiorino, M. Valente, L. Ferri and C. Gregolin, Biochim. Biophys. Acta, Lipids Lipid Metab., 1982, 710, 197–211.
297. Y. Zou, H. Li and E. T. Graham, et al. , Nat. Chem. Biol., 2020, 16, 302–309.
298. A. Anandhan, M. Dodson, A. Shakya, J. Chen, P. Liu, Y. Wei, H. Tan, Q. Wang, Z. Jiang, K. Yang, J. G. Garcia, S. K. Chambers, E. Chapman, A. Ooi, Y. Yang-Hartwich, B. R. Stockwell and D. D. Zhang, Sci. Adv., 2023, 9, eade9585.
299. W. Hou, Y. Xie, X. Song, X. Sun, M. T. Lotze, H. J. Zeh Iii, R. Kang and D. Tang, Autophagy, 2016, 12, 1425–1428.
300. M. Gao, P. Monian, Q. Pan, W. Zhang, J. Xiang and X. Jiang, Cell Res., 2016, 26, 1021–1032.
301. K. Hattori, H. Ishikawa, C. Sakauchi, S. Takayanagi, I. Naguro and H. Ichijo, EMBO Rep., 2017, 18, 2067–2078.
302. Y. Yu, L. Jiang and H. Wang, et al. , Blood, 2020, 136, 726–739.
303. B. Zhou, J. Y. Zhang and X. S. Liu, et al. , Cell Res., 2018, 28, 1171–1185.
304. Y. Chen, W. Li, S. Kwon, Y. Wang, Z. Li and Q. Hu, J. Am. Chem. Soc., 2023, 145, 9815–9824.
305. J. Feng, Z. X. Wang, J. L. Bin, Y. X. Chen, J. Ma, J. H. Deng, X. W. Huang, J. Zhou and G. D. Lu, Cancer Lett., 2024, 587, 216728.
306. B. Fernández, E. Fdez, P. Gómez-Suaga, F. Gil, I. Molina-Villalba, I. Ferrer, S. Patel, G. C. Churchill and S. Hilfiker, Autophagy, 2016, 12, 1487–1506.
307. Y. Wang, M. Wang, Y. Liu, H. Tao, S. Banerjee, S. Srinivasan, E. Nemeth, M. J. Czaja and P. He, Redox Biol., 2022, 55, 102407.
308. E. J. Ge, A. I. Bush and A. Casini, et al. , Nat. Rev. Cancer, 2022, 22, 102–113.
309. H. M. Alvarez, Y. Xue, C. D. Robinson, M. A. Canalizo-Hernández, R. G. Marvin, R. A. Kelly, A. Mondragón, J. E. Penner-Hahn and T. V. O’Halloran, Science, 2010, 327, 331–334.
310. D. Cen, D. Brayton, B. Shahandeh, F. L. Meyskens and P. J. Farmer, J. Med. Chem., 2004, 47, 6914–6920.
311. N. C. Yip, I. S. Fombon and P. Liu, et al. , Br. J. Cancer, 2011, 104, 1564–1574.
312. R. Gupta, V. Luxami and K. Paul, Bioorg. Chem., 2021, 108, 104633.
313. L. I. Victoriano, Coord. Chem. Rev., 2000, 196, 383–398.
314. K. G. Daniel, D. Chen, S. Orlu, Q. C. Cui, F. R. Miller and Q. P. Dou, Breast Cancer Res., 2005, 7, R897.
315. Z. Zhang, H. Wang, M. Yan, H. Wang and C. Zhang, Mol. Med. Rep., 2017, 15, 3–11.
316. T. Hirschhorn and B. R. Stockwell, Free Radical Biol. Med., 2019, 133, 130–143.
317. X. Ren, Y. Li and Y. Zhou, et al. , Redox Biol., 2021, 46, 102122.
318. Y. Shang, M. Luo, F. Yao, S. Wang, Z. Yuan and Y. Yang, Cell. Signalling, 2020, 72, 109633.
319. G. Lei, Y. Zhang and P. Koppula, et al. , Cell Res., 2020, 30, 146–162.
320. M. Yang, X. Wu and J. Hu, et al. , J. Hepatol., 2022, 76, 1138–1150.
321. B. Halliwell and J. M. C. Gutteridge, Biochem. J., 1984, 219, 1–14.
322. T. Tsang, J. M. Posimo, A. A. Gudiel, M. Cicchini, D. M. Feldser and D. C. Brady, Nat. Cell Biol., 2020, 22, 412–424.
323. F. Wan, G. Zhong and Z. Ning, et al. , Ecotoxicol. Environ. Saf., 2020, 190, 110158.
324. H. Guo, Y. Ouyang and H. Yin, et al. , Redox Biol., 2022, 49, 102227.
325. K. A. Peña and K. Kiselyov, Biochem. J., 2015, 470, 65–76.
326. L. Chen, N. Li and M. Zhang, et al. , Angew. Chem., Int. Ed., 2021, 60, 25346–25355.
327. W. Chen, X. Wang and B. Zhao, et al. , Nanoscale, 2019, 11, 12983–12989.
328. Y. Zhang, Q. Jia and J. Li, et al. , Adv. Mater., 2023, 35, e2305073.
329. G. Zhu, Y. Xie, J. Wang, M. Wang, Y. Qian, Q. Sun, Y. Dai and C. Li, Adv. Mater., 2024, 36, 2409066.
330. G. Briassoulis, P. Briassoulis, S. Ilia, M. Miliaraki and E. Briassouli, Antioxidants, 2023, 12, 1942.
331. E. Bafaro, Y. Liu, Y. Xu and R. E. Dempski, Signal Transduction Targeted Ther., 2017, 2, 17029.
332. B. Chen, P. Yu and W. N. Chan, et al. , Signal Transduction Targeted Ther., 2024, 9, 6.
333. P. Chandler, B. S. Kochupurakkal, S. Alam, A. L. Richardson, D. I. Soybel and S. L. Kelleher, Mol. Cancer, 2016, 15, 2.
334. W. Alker and H. Haase, Nutrients, 2018, 10, 976.
335. K. Thambiayya, A. M. Kaynar, C. M. S. Croix and B. R. Pitt, Pulm. Circ., 2012, 2, 443–451.
336. S. J. Lee, M. H. Park, H. J. Kim and J. Y. Koh, Glia, 2010, 58, 1186–1196.
337. L. Tan, C. He, X. Chu, Y. Chu and Y. Ding, Chem. Eng. J., 2020, 395, 125177.
338. F. Muhammad, M. Guo, W. Qi, F. Sun, A. Wang, Y. Guo and G. Zhu, J. Am. Chem. Soc., 2011, 133, 8778–8781.
339. J. P. Liuzzi and R. Pazos, J. Trace Elem. Med. Biol., 2020, 62, 126636.
340. H. Fang, S. Geng and M. Hao, et al. , Nat. Commun., 2021, 12, 109.
341. A. Lahiri and C. Abraham, Gastroenterology, 2014, 147, 835–846.
342. K. M. Taylor, P. Vichova, N. Jordan, S. Hiscox, R. Hendley and R. I. Nicholson, Endocrinology, 2008, 149, 4912–4920.
343. K. W. Kim, C. K. Speirs, D. K. Jung and B. Lu, J. Thorac. Oncol., 2011, 6, 1542–1552.
344. M. Farasat, F. Niazvand and L. Khorsandi, Biologia, 2020, 75, 161–174.
345. Y. Li, C. Jiang, X. Zhang, Z. Liao, L. Chen, S. Li, S. Tang, Z. Fan and Q. Zhang, Cancer Nanotechnol., 2022, 13, 3.
346. P. H. Chen, J. Wu, Y. Xu, C. K. C. Ding, A. A. Mestre, C. C. Lin, W. H. Yang and J.-T. Chi, Cell Death Dis., 2021, 12, 198.
347. P. Zheng, B. Ding, G. Zhu, M. Wang, C. Li and J. Lin, Chem. Eng. J., 2022, 450, 137967.
348. B. Ding, H. Chen, J. Tan, Q. Meng, P. Zheng, P. A. Ma and J. Lin, Angew. Chem., Int. Ed., 2023, 62, e202215307.
349. X. Su, B. Liu, W. J. Wang, K. Peng, B. B. Liang, Y. Zheng, Q. Cao and Z. W. Mao, Angew. Chem., Int. Ed., 2023, 62, e202216917.
350. B. Xia, S. Fang, X. Chen, H. Hu, P. Chen, H. Wang and Z. Gao, Cell Res., 2016, 26, 517–528.
351. X. Shao, C. Qu, G. Song, B. Wang, Q. Tao, R. Jia, J. Li, J. Wang and H. An, Adv. Funct. Mater., 2023, 33, 2306585.
352. J. He, X. Ma and J. Zhang, et al. , Food Chem. Toxicol., 2024, 184, 114322.
353. P. Wang, C. Liang, J. Zhu, N. Yang, A. Jiao, W. Wang, X. Song and X. Dong, ACS Appl. Mater. Interfaces, 2019, 11, 41140–41147.
354. N. de Dios, R. Riedel and M. Schanton, et al. , Biol. Reprod., 2024, 111, 708–722.
355. B. Deka, T. Sarkar, A. Bhattacharyya, R. J. Butcher, S. Banerjee, S. Deka, K. K. Saikia and A. Hussain, Dalton Trans., 2024, 53, 4952–4961.
356. X. Zhao, Y. Wang, T. Zhu, H. Wu, D. Leng, Z. Qin, Y. Li and D. Wu, Int. J. Nanomed., 2022, 17, 5187–5205.
357. M. T. Nunez and C. Hidalgo, Front. Neurosci., 2019, 13, 48.
358. C. Manzl, J. Enrich, H. Ebner, R. Dallinger and G. Krumschnabel, Toxicology, 2004, 196, 57–64.
359. Z. Pan, S. Choi, H. Ouadid-Ahidouch, J.-M. Yang, J. H. Beattie and I. Korichneva, Front. Biosci.-Landmark, 2017, 22, 623–643.
360. Y. Jiang, K. Shao, F. Zhang, T. Wang, L. Han, X. Kong and J. Shi, Aggregate, 2023, 4, e321.
361. C. A. Blomeyer, J. N. Bazil, D. F. Stowe, R. K. Dash and A. K. S. Camara, J. Bioenerg. Biomembr., 2016, 48, 175–188.
362. M. Tan, G. Cao and R. Wang, et al. , Nat. Nanotechnol., 2024, 19, 1903–1913.
363. Y. Li, Y. Du, Y. Zhou, Q. Chen, Z. Luo, Y. Ren, X. Chen and G. Chen, Cell Commun. Signaling, 2023, 21, 327.
364. K. E. Splan, S. R. Choi, R. E. Claycomb, I. K. Eckart-Frank, S. Nagdev and M. E. Rodemeier, JBIC, J. Biol. Inorg. Chem., 2023, 28, 485–494.
365. C. Liu, L. Guo, Y. Wang, J. Zhang and C. Fu, Coord. Chem. Rev., 2023, 494, 215332.
366. W. Park, S. Wei, B.-S. Kim, B. Kim, S.-J. Bae, Y. C. Chae, D. Ryu and K.-T. Ha, Exp. Mol. Med., 2023, 55, 1573–1594.
367. L. Y. Wang, X. J. Liu and Q. Q. Li, et al. , Mol. Cell. Biochem., 2023, 479, 2255–2272.
368. M. N. Messmer, A. G. Snyder and A. Oberst, Cell Death Differ., 2019, 26, 115–129.

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