Advances and therapeutic potential of ferritin-involved drug delivery systems for ferroptosis-targeted therapy

Abstract

Ferroptosis, a regulated cell death pathway characterized by iron dysregulation and lipid peroxide accumulation, has emerged as a pivotal target in the treatment of cancer and other diseases. As a natural iron storage protein in organisms, ferritin (Fn) is involved in regulating intracellular iron homeostasis through processes such as iron transport, storage, and ferritinophagy, which in turn significantly influence the Fenton reaction, making it closely related to the occurrence of ferroptosis. Additionally, due to the unique cavity structure of ferritin nanocages, their excellent biocompatibility and their specific binding ability for the highly expressed transferrin receptor 1 (TfR1) on the surface of tumor cells, ferritin nanocages have been extensively explored in the design and development of drug delivery systems (DDS). Given the above background, this paper reviews the novel mechanisms of ferroptosis and the research advancements in the related diseases and drugs. It further explores the structure and application of ferritin (including DDS design and vaccine development) and emphasizes the construction of DDSs regulating ferroptosis through utilizing ferritin nanocages as carriers or by targeting the disruption of endogenous ferritin, with the expectation of providing a reference for the development of safer and more effective nanoformulations.

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1. Introduction

Cell death constitutes a fundamental biological process that is indispensable for organismal growth, developmental patterning, and the maintenance of internal environmental homeostasis. Traditionally, cell death is classified into two primary categories: regulated cell death (RCD)—also termed programmed cell death—and accidental cell death (ACD).¹ RCD is governed by tightly controlled molecular signaling cascades, whereas ACD results from acute, uncontrolled physical or chemical insults that disrupt cellular integrity (Table 1).

Table 1 Comparison of the characteristics of different cell death types

Types of cell death	Necroptosis	Autophagy	Apoptosis	Pyroptosis	Ferroptosis
Biochemical features	Decrease in ATP levels, RIPK1/RIPK3/MLKL pathway activation, etc.	LC3 lipidation, autophagosome formation, and enhanced lysosomal activity, etc.	Phosphatidylserine translocation, DNA fragmentation, etc.	Inflammasome assembly, accompanied by GSDMD cleavage, as well as IL-1β and IL-18 release, etc.	Iron overload, ROS accumulation, system Xc^− inhibition and GSH depletion, etc.
Morphological features	Plasma membrane rupture, swelling and deformation of cells and organelles, and content release.	Massive autophagic vacuolization	Cytoplasm shrinkage, chromatin condensation, DNA damage, cellular blebbing, the appearance of apoptotic bodies, etc.	Cell swelling, membrane rupture and blebbing, DNA damage, chromatin condensation, the appearance of pyroptotic bodies, etc.	Rupture of the cell membrane, mitochondrial atrophy, decrease or disappearance of mitochondrial cristae, etc.
Key regulatory mechanisms	RIPK1, RIPK3, MLKL, CYLD, cIAP1/2, caspase-8, etc.	AMPK, mTOR, VPS34, etc.	BCL-2, Bid, caspases, Bax, Bak, etc.	GSDMD, IL-1β, IL-18, caspase-1/4/5/11, etc.	ALOX, SLC7A11, TfR1, GPX4, p53, ACSL4, LPCAT3, etc.
Related diseases	Cancers, neurodegenerative diseases, kidney and liver diseases, etc.	Cancers, neurodegenerative diseases, hepatic and metabolic disorders, etc.	Cancers, neurodegenerative diseases, cardiovascular disorders, autoimmune diseases, etc.	Cancers, inflammatory diseases, etc.	Cancers, neurodegenerative diseases, ischemia/reperfusion injury, autoimmune diseases, etc.
Ref.	6 and 7	1, 8 and 9	10–12	13 and 14	15 and 16

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Among these, ferroptosis, an iron-dependent mode of programmed cell death, is characterized by disturbances in iron metabolism as well as the production and accumulation of lipid peroxides. Since Dixon et al. initially introduced the concept in 2012, research on the mechanism of ferroptosis and other related aspects has progressively expanded, refined, and enhanced over recent years (Fig. 1).² A growing body of experimental evidence highlights that ferroptosis is a critical mechanism underlying the development and treatment of various diseases, including cancers, neurodegenerative diseases, metabolic disorders, and ischemia/reperfusion injury.³ Therefore, the development of ferroptosis-related drugs for disease treatment has become a current research hotspot in the field of pharmacy. Despite the evidence from studies showing that marketed drugs, including cisplatin and sorafenib (SRF), are capable of inducing ferroptosis pathways and thus exerting anti-tumor therapeutic effects, the application of these drugs is still limited to some extent by factors such as a lack of targeting, small drug loading, and low bioavailability.^4,5 The development of more precisely targeted nanoformulations and drug delivery systems (DDSs) to meet the rich clinical therapeutic needs has become a key research direction for drug formulation.

Fig. 1 Timeline of progress in ferroptosis mechanism research.

Ferritin (Fn) is a natural iron storage protein found in organisms, consisting of heavy chain (FTH1) and light chain (FTL) subunits. Owing to its good biocompatibility, inherent cavity structure for drug loading, good pH and thermal stability, reversible self-assembly, easily modifiable structure, and capacity to selectively target tumor cells that overexpress transferrin receptor 1 (TfR1), it has been extensively utilized in recent years in studies related to drug delivery. Meanwhile, the evolving understanding of the ferroptosis mechanism has increasingly revealed that ferritin, a key regulator of intracellular iron metabolism, has a substantial impact on ferroptosis. Consequently, the design of DDSs based on ferritin nanocages as carriers to regulate intracellular ferroptosis and mediate endogenous ferritinophagy is increasing and showing incomparable advantages.

Based on the above background, this article comprehensively reviews the latest research progress on the ferroptosis mechanism and the related diseases and drugs and focuses on the ferritin involvement in ferroptosis-based DDSs designed for the treatment of diverse diseases, with the hope of providing a reference and guidance for the subsequent scientific research and clinical development of safer and more effective ferroptosis-targeted therapeutic strategies.

2. Ferroptosis and diseases

2.1. Mechanisms of ferroptosis

Ferroptosis is a class of iron-dependent cell death pathways in regulatory cell death, which, in essence, is a disruption of intracellular redox homeostasis. It is characterized specifically by the overwhelming accumulation of lipid peroxides in the cell membrane due to multiple pathways involving iron, ultimately resulting in plasma membrane rupture and consequent cell death.¹⁷ Although the precise mechanism of ferroptosis remains incompletely understood, evidence suggests that numerous metabolic pathways, particularly those involving iron, lipid, and amino acid metabolism, as well as degradation pathways (macroautophagy/autophagy and the ubiquitin-proteasome system), can modulate intracellular iron accumulation or lipid peroxidation (LPO) either directly or indirectly, thereby orchestrating the intricate process of ferroptosis (Fig. 2).¹⁸

Fig. 2 Molecular mechanisms of ferroptosis.

2.1.1. Mechanisms of iron metabolism. As the name “ferroptosis” implies, iron, an essential element in the human body, plays a crucial role in the process of cellular ferroptosis through its metabolism. Under physiological conditions, the majority of cellular iron uptake occurs through transferrin-bound iron and non-transferrin-bound iron (NTBI). In the former case, ferric ions (Fe³⁺) bind to transferrin (Tf-Fe₂) and are internalized into the cell via endocytosis, a process mediated by TfR1 expressed on the cell membrane, and subsequently form endosomes. Due to the alteration in the pH environment, Fe³⁺ is released from transferrin (Tf) within the endosome. Afterward, the metal reductase six-transmembrane epithelial antigen of prostate3 (STEAP3) reduces Fe³⁺ to Fe²⁺, which is then transported into the labile iron pool via divalent metal transporter1 (DMT1), thus completing the process of cellular Tf-mediated iron uptake.¹⁹ While iron is overloaded, cells increase the uptake of NTBI through metal transporters such as SLC39A14.²⁰ Excessively absorbed Fe²⁺ may enter ferritin via 3-fold symmetry channels, subsequently binding to the center of ferroxidase and undergoing oxidation.²¹ Another fraction of Fe²⁺ can be transported out of the cell via Ferroportin1 (Fpn1/SLC40A1). Once exported, the iron is catalyzed by ceruloplasmin (Cp) to Fe³⁺ and subsequently enters the bloodstream.²² Thus, these processes help maintain intracellular iron homeostasis and restrict the occurrence of ferroptosis. Meanwhile, the iron-responsive element/iron-regulatory protein (IRE/IRP) system is capable of responding to intracellular iron levels and participating in the regulation of iron metabolism by affecting the mRNA expression of iron-associated proteins, such as FTH1/FTL, TfR1, and Fpn1.²³ When intracellular iron is deficient or in a high iron demand environment, the stored iron is released through nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy degradation, allowing the intracellular iron content to be maintained in a dynamic equilibrium process.²⁴ However, when the iron metabolism is disordered and the intracellular iron overload occurs, excessive free Fe²⁺ triggers the Fenton reaction (Fe²⁺ + H₂O₂ → Fe³⁺ + OH⁻ + ˙OH), leading to the generation of numerous hydroxyl radicals (˙OH), which cause LPO and induce cell ferroptosis. Therefore, the processes of intracellular iron metabolism, including iron uptake, storage, and utilization, as well as ferritinophagy degradation, constitute an important link in the process of ferroptosis onset.

2.1.2. Mechanisms of lipid metabolism. LPO is one of the most important markers of ferroptosis. It usually occurs through enzymatic reactions involving lipoxygenase (LOX), cyclooxygenase (COX), cytochrome P450s (CYPs), or non-enzymatic reactions, such as free radical-induced peroxidation and autoxidation.²⁵ Hydroperoxides generated on polyunsaturated fatty acid (PUFA) chains found in membrane phospholipids were proven to be vital in the occurrence of cellular ferroptosis.²⁶ In addition to ferrous iron (Fe²⁺) mediating the Fenton reaction to produce ˙OH, resulting in LPO as mentioned in “Iron metabolism”, intracellular arachidonic acid (AA) and adrenic acid (AdA), the predominant substrates for LPO, can be catalyzed by acyl-CoA synthetase long-chain family member 4 (ACSL4) to produce AA-CoA or AdA-CoA (PUFA-CoA), and further esterified to PE-AA or PE-AdA (PUFA-PL) by lysophosphatidylcholine acyltransferase 3 (LPCAT3).^27,28 Eventually, the oxidation of the aforementioned products by arachidonate lipoxygenases (ALOXs) and cytochrome P450 oxidoreductase (POR) generates cytotoxic PE-AA-OOH or PE-AdA-OOH (PUFA-PL-OOH), leading to cell membrane damage and consequently enhancing ferroptosis sensitivity.²⁹

Normally, strict intracellular mechanisms exist to limit lipid peroxide accumulation to avoid ferroptosis. In this regard, glutathione peroxidase 4 (GPX4) serves as a key factor in converting toxic lipid hydroperoxide (LOOH) into benign lipid alcohols (LOH), preventing ferroptosis caused by the accumulation of lipid peroxides.³⁰ In addition, certain endogenous free radical-trapping antioxidants (RTAs), such as ubiquinone (CoQ), can be synergistically reduced to ubiquinol (CoQH2) in response to the CoQ oxidoreductase ferroptosis suppressor protein 1 (FSP1), exerting a parallel effect on ferroptosis inhibition to that of GPX4.³¹ Similarly, CoQ was found in mitochondria in 2021 to be equally converted to CoQH2 by mitochondrial dihydroorotate dehydrogenase (DHODH), thus alleviating the burden of cellular ferroptosis.³² In addition to the aforementioned mechanisms, GTP cyclohydrolase 1 (GCH1) has been demonstrated to inhibit LPO, thereby affecting ferroptosis by modulating the production of the antioxidant tetrahydrobiopterin (BH4).^33,34 Moreover, research has found that PUFAs are more susceptible to LPO compared to monounsaturated fatty acids (MUFAs); thus, the MUFA to PUFA ratio is an additional determinant of ferroptosis sensitivity.³⁵ Previous studies have shown that MUFA can inhibit ferroptosis in the presence of acyl-CoA synthetase long-chain family member 3 (ACSL3) by inhibiting the level of reactive oxygen species (ROS) on the plasma membrane and reducing the proportion of oxidizable PUFA on phospholipids.³⁶ In a new study in 2023, Liang et al. demonstrated that MBOAT1/MBOAT2, members of the lysophosphatidylcholine acyltransferase family, controlled by sex hormone signaling, were able to inhibit ferroptosis by remodeling the lipid composition of the cell membrane and replacing readily oxidizable PUFAs with synthetic MUFAs.³⁷ This further elucidates the regulatory pathways of ferroptosis by modulating lipid metabolism and highlights the robustness of intracellular antioxidant defense mechanisms.

2.1.3. Mechanisms of amino acid metabolism. The metabolic pathways involving amino acids such as glutamate (Glu), cystine (Cys2), and cysteine (Cys) also contribute to the induction of ferroptosis. Specifically, the cystine/glutamate antiporter (System Xc⁻) located on the cell membrane is an amino acid transport protein complex composed of the catalytic subunit SLC7A11 and the regulatory subunit SLC3A2, which functions to import Cys2 and export Glu, driving the synthesis of the intracellular antioxidant glutathione (GSH).^38,39 In this process, Cys2 is internalized by the cell via the System Xc⁻ transporter and then reduced to Cys by the GSH and thioredoxin reductase 1 (TXNRD1).⁴⁰ Cys, as the rate-limiting precursor for the synthesis of the most important intracellular antioxidant GSH, is synthesized into endogenous GSH under the mediation of glutamate-cysteine ligase (GCL).^41,42 Furthermore, GSH, acting as a vital cofactor for GPX4, effectively mitigates oxidative stress and prevents ferroptosis by catalyzing the reduction of lipid hydroperoxides (LOOH) to their corresponding alcohols (LOH), a process detailed in the preceding section on lipid metabolism. During this process, glutathione disulfide (GSSG) produced by oxidation is converted to reduced GSH under the action of GSH reductase and NADPH/H⁺ to achieve the GSH/GSSG redox cycle.⁴³ This transformation relationship helps to maintain the balance of metabolic processes and build a defense against ferroptosis within the cell.

2.1.4. p53 pathway. The p53 gene has been widely used in cancer-related research since its discovery in 1979.⁴⁴ Recent studies have revealed that p53 can modulate ferroptosis in a bidirectional manner by regulating metabolic pathways, including iron, lipids, ROS, and amino acids through classical pathways.⁴⁵ In the mechanism of amino acid metabolism, it was demonstrated that p53 inhibits cystine uptake by affecting the expression of SLC7A11, a key component of the cystine/glutamate antiporter system at the membrane surface, which is used to control GSH production to enhance cellular susceptibility to ferroptosis.⁴⁶ Based on this study, a follow-up investigation further reported that p53-mediated downregulation of SLC7A11 enhances the LPO activity of lipoxygenase ALOX12, positively driving ferroptosis.⁴⁷ Moreover, Ou et al. indicated that p53 was able to contribute to ferroptosis by inducing the upregulation of spermine/spermine N¹-acetyltransferase 1 (SAT1) expression and increasing ALOX15 expression, reflecting the multiple pathways of positive induction of ferroptosis in which p53 is involved.⁴⁸

As a bi-directional regulatory pathway for ferroptosis, other findings suggest that the p53 pathway exerts an inhibitory effect in the process of ferroptosis. For instance, p53 has been discovered to inhibit ferroptosis by blocking dipeptidyl peptidase 4 (DPP4) activity.⁴⁹ Other studies revealed that p53 can induce p21, which delays the occurrence of ferroptosis by reallocating serine to synthesize GSH.^50,51 These studies highlight the multifaceted and complicated involvement of p53 mediation in the ferroptosis mechanism.

2.2. Related diseases

With the deepening of research on ferroptosis, an increasing body of evidence has shown that it plays a considerable role in the development and treatment of a wide range of diseases, including cancers, neurodegenerative diseases, and metabolic disorders (Fig. 3). Therefore, ferroptosis is regarded as a double-edged sword, being a potential therapeutic strategy for inducing tumor cell death in cancer treatment, while contributing to the development of a variety of diseases, such as neurodegeneration and ischemia/reperfusion injury, by exacerbating cellular damage and thus driving disease progression.

Fig. 3 Diseases associated with ferroptosis.

2.2.1. Cancers. Tumor cells exhibit a higher iron requirement compared to normal cells. Studies have shown that TfR1, the primary iron uptake pathway in cancer cells, is upregulated in many tumors, including breast, lung, and bladder cancer.⁵² This upregulation increases intracellular iron levels, creating a natural iron pool that provides a favorable basis for ferroptosis-based cancer therapies. At the same time, several studies have shown that the treatment of tumors through ferroptosis regulation can reverse the resistance of traditional chemotherapy, targeted therapy, and immunotherapy during treatment, which collectively provide innovative perspectives for the advancement of ferroptosis-mediated tumor therapies.⁵³

However, tumors are cunning; in order to counteract the cellular damage triggered by ferroptosis, cancer cells have evolved a diverse array of mechanisms that extend beyond the classical regulatory pathways. These advanced strategies, which include restricting the synthesis and peroxidation of PUFA-PL, controlling the labile iron pool within cells, and upregulating ferroptosis defense mechanisms, empower cancer cells to effectively evade ferroptosis, thus driving tumor progression and metastasis.⁵⁴ Specifically, hypoxia-inducible factor 1α (HIF-1α), which is synthesized in solid tumors under hypoxic conditions, has been shown to enhance cystine uptake by upregulating the expression of SLC1A1 and promoting lactate production in a pH-dependent manner, both of which collectively drive ferroptosis resistance.⁵⁵ On the other hand, Chen et al. found that Ca²⁺-independent phospholipase A₂β (iPLA₂β) is overexpressed in a variety of cancers, including kidney renal clear cell carcinoma (RCC) and acute myeloid leukemia (AML), and this expression enables cancer cells to resist ferroptosis by detoxifying lipid peroxides.⁵⁶ Furthermore, nuclear factor erythroid 2-related factor 2 (Nrf2) enhances survival adaptation to ferroptosis in cancer cells by up-regulating FSP1 in KEAP1-mutant lung cancer.⁵⁷ A recent study reported that tumor cells can activate the Nrf2-SLC7A11 pathway by utilizing the SLC13A3 from tumor-associated macrophages (TAMs) to uptake itaconate, thereby achieving endogenous evasion of immune-mediated ferroptosis.⁵⁸ These findings indicate that tumor cells have evolved a more robust resistance to ferroptosis. Therefore, breaking down the ferroptosis defense mechanisms of tumor cells by introducing ferroptosis inducers and other means has become an effective strategy for ferroptosis-based cancer therapy.

2.2.2. Neurodegenerative diseases. Neurodegenerative diseases (ND) represent a category of neurological disorders characterized by the progressive degeneration and loss of neurons, and include Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Accumulating evidence from various studies has demonstrated that iron accumulation and LPO, accompanied by the reduction of GPX4 and GSH, are closely linked to the progression of these diseases, implying that ferroptosis may serve as a critical mechanism in the development of neurodegenerative diseases.⁵⁹

Alzheimer's disease, the most prevalent chronic and irreversible central neurodegenerative disorder, is characterized by progressive declines in memory, logical reasoning, and language abilities, along with the accumulation of amyloid-β and tau proteins in the brain.^60,61 In a highly similar correlation with ferroptosis characteristics, the disruption of iron homeostasis, glutamate excitotoxicity, and accumulation of lipid ROS in the brain were observed in both AD models and patients, and studies have confirmed a positive correlation between elevated levels of iron in the brain and the progression of the disease and cognitive decline.^62,63 Previous research has indicated that the reduction or deletion of Fpn1 exacerbates memory impairment in AD model mice and patients by promoting ferroptosis.⁶⁴ It is also noteworthy that the iron chelator Deferoxamine (DFO), acting as a ferroptosis inhibitor, has been shown in a single-blind randomized study to reduce the clinical progression rate of AD dementia, effectively slowing the progression of the disease.⁶⁵

Following AD, the second most common neurodegenerative disease, PD, exhibits the typical features of loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the formation of Lewy bodies, which is the main cause of the emergence of motor and non-motor symptoms, such as resting tremor, rigidity, sleeping disturbances, and cognitive impairment.⁶⁶ Similar to AD, biochemical features consistent with ferroptosis are observed in the substantia nigra of PD patients, including abnormal iron accumulation, decreased GSH levels, and increased lipid peroxides.⁶² In a recent study, the design of DFO integrated nanosheets (BDPR NSs) proposed by Lei et al. effectively reduced the levels of iron and ROS in the brain and alleviated the loss of dopaminergic neurons to mitigate related behavioral symptoms by inhibiting ferroptosis, confirming the validity and feasibility of treating neurodegenerative disorders, such as AD and PD, by suppressing ferroptosis in the neuronal cells.⁶⁷

2.2.3. Ischemia/reperfusion injury. Ischemia/reperfusion injury (I/R) is a secondary injury caused by blood flow recovery and reoxygenation after ischemia in cellular tissues. It is a major contributor to cell death and organ damage and is commonly seen in acute kidney injury (AKI), acute myocardial infarction (AMI), ischemic stroke (IS), and other diseases.^68,69 Quite generally, in myocardial ischemia-reperfusion (MI/R) due to AMI, it has been demonstrated that ALOX-15/15-HpETE drives the I/R process by inducing ferroptosis in cardiomyocytes.⁷⁰ In the latest study, Wang et al. further enriched the potential mechanism of the stimulator of interferon genes (STING) involved in ferroptosis-related MI/R injury; that is, the MI/R process is accompanied by STING activation, which targets and binds to GPX4, leading to GPX4 degradation mediated by autophagosome-lysosome fusion.⁷¹ This process amplifies ferroptosis and exacerbates MI/R injury, further strengthening the link between ferroptosis and MI/R.

IS is a highly disabling acute cerebrovascular disease, and some studies have reported that IS is accompanied by typical biochemical features of ferroptosis, including LPO, iron overloading, and altered expression of ferroptosis-related genes such as GPX4 and ACSL4.⁷² Severe ferroptosis will cause irreversible damage to neuronal cells, which can adversely impact the prognosis of patients. The study conducted by Cui et al. revealed that the inhibition of ACSL4 mediated by HIF-1α in the early stages of ischemic stroke (IS) serves to protect cells from ferroptosis injury.⁷³ In a more recent investigation, it was reported that Nrf2 attenuates neuronal ferroptosis and oxidative stress associated with IS in a manner that up-regulates GPX4 and System Xc⁻ expression.⁷⁴

2.2.4. Metabolic disorder. Among the metabolic diseases, it has been widely recognized that ferroptosis of pancreatic β-cells is one of the major influencing factors in the development of type 2 diabetes mellitus (T2DM), which results in reduced insulin secretion.⁷⁵ Moreover, a high glucose environment stimulates cellular lipid ROS accumulation and downregulates GSH levels, further exacerbating ferroptosis and causing a vicious cycle.⁷⁶ Ren et al. identified that in diabetic nephropathy, a high-glucose environment affects cysteine uptake by promoting BAP1 expression and inhibiting H2Aub deubiquitination on SLC7A11, which drives the process of LPO in podocytes and induces ferroptosis.⁷⁷ Similarly, in T2DM-induced osteoporosis, high-glucose conditions contribute to lipid peroxide accumulation and downregulate the expression of SLC7A11 and GPX4, triggering osteoblast ferroptosis.⁷⁸ These research findings highlight the substantial impact of ferroptosis on the development and progression of diabetes and its complications. In addition, the findings of Sun et al. reported that metformin, a first-line drug for T2DM, was able to attenuate lipid-associated ROS production and restore insulin release in the pancreatic islets of model mice through GPX4/ACSL4 axis modulation, further revealing a new mechanism of metformin in the treatment of T2DM through the inhibition of ferroptosis.⁷⁹

2.2.5. Other diseases. In other diseases, such as the degenerative joint disease osteoarthritis (OA), studies have revealed that iron accumulation and alterations in the expression of iron-related proteins are frequently observed in the serum, plasma, synovial fluid, and cartilage of patients with OA.⁸⁰ Meanwhile, classical features of ferroptosis, such as iron accumulation and LPO, were identified in the OA model. In 2022, Guo et al. confirmed that DFO could inhibit ferroptosis in chondrocytes and promote the activation of the Nrf2 antioxidant system.⁸¹ In the same year, another study reported significant down-regulation of GPX4 expression levels accompanied by ECM degradation in the articular cartilage of 55 patients with OA, while the introduction of Fer-1 with DFO protected against OA, further confirming the strong correlation between ferroptosis and the progression of OA.⁸²

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by polyarticular inflammation. Although the pathogenesis is not fully understood, evidence suggests that RA patients exhibit elevated serum and synovial iron levels, increased ROS accumulation, and reduced levels of antioxidants such as GSH, which indicates that ferroptosis plays a crucial role in RA progression.⁸³ Meanwhile, iron deposition has been shown to exacerbate arthritis by inducing macrophage ferroptosis in localized RA lesions.⁸⁴ In some cases, ferroptosis exerts a therapeutic effect in RA, as reported in earlier findings, where activated synovial fibroblasts aggravated the development of inflammation in RA by releasing inflammatory cytokines, proangiogenic factors, etc. Based on the above background, Wu et al. confirmed that treatment with low-dose imidazole ketone erastin (IKE) and TNF antagonists in a collagen-induced arthritis (CIA) model mouse was effective in promoting ferroptosis of fibroblasts and delaying RA progression.⁸⁵

3. Ferroptosis-related drugs and regulators

3.1 Ferroptosis inducers

Ferroptosis inducers can be used in the adjuvant treatment of tumors to effectively optimize cancer efficacy by inhibiting acquired tumor cell resistance.⁸⁶ Based on the differences in the induction mechanisms, they can be classified into several categories, such as System Xc⁻ inhibitors, GPX4 inhibitors, and iron metabolism inducers (Table 2).⁸⁷

Table 2 Overview of the main categories of ferroptosis regulators^108–111

Ferroptosis regulators	Classification of mechanisms		Representative drugs
Ferroptosis inducers	System Xc^− inhibition, blocking cystine inputs		Erastin and its derivatives, SSZ, SRF, etc.
	Inhibition of GPX4		RSL3, DPI7 (ML162), FIN56, etc.
	GSH depletion		DPI2, cisplatin, buthionine sulfoximine, etc.
	Regulation of iron metabolism	Iron loading	Heme, ferrous ammonium sulfate, ferrous chloride, etc.
		Induction of ferritinophagy	DHA, PPI, Sal, etc.
Ferroptosis inhibitors	Reduces iron content (iron chelator)		DFO, DFP, deferasirox (DFX), ciclopirox (CPX), AKI-02, etc.
	LOX inhibitors		Zileuton (A-64077), baicalein, docebenone (AA-861), BWA4C, PD-146176, etc.
	RTAs	Endogenous RTA	Fer-1, Lip-1, XJB-5-131, phenothiazine, etc.
		Synthetic RTA	α-tocopherol (Vitamin E), BH4, Vitamin K, etc.
	Inhibit ACSL4		Troglitazone (TRO), rosiglitazone (ROSI), pioglitazone (PIO), etc.
	Effects on the GSH/GPX4 axis		PKUMDL-LC-101, PKUMDL-LC-101-D04, disulfiram(DSF), fursultiamine, Se, etc.

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System Xc⁻ inhibitors mainly include Erastin and its derivatives, sulfasalazine (SSZ), and SRF. Such inducers trigger ferroptosis by inhibiting System Xc⁻, affecting cystine uptake, and depleting intracellular GSH. Erastin, a representative of this class of drugs, has been widely used in laboratory ferroptosis-related studies since its first discovery by Dolma in 2003.⁸⁸ In the last study, Yan et al. clarified the site of action of Erastin using cryogenic electron microscopy (cryo-EM) and successfully revealed its effective induction of ferroptosis through the binding of chlorophenoxy to the PHE254 residue in the transmembrane 6b structural domain of SLC7A11.⁸⁹

GPX4 is another target of ferroptosis inducers; inducers such as RSL3, FIN56, and DPI7 can achieve ferroptosis induction by affecting GPX4. Previously, it was believed that RSL3 promotes ROS accumulation and increases cell sensitivity to ferroptosis by affecting GPX4 expression in the treatment of colorectal cancer, prostate cancer, and other tumors.^90,91 However, the results of a new study point to the possibility that RSL3 may not directly affect GPX4, but rather achieve effective induction of ferroptosis through the inhibition of TXNRD1, which needs to be further evaluated and demonstrated.⁹² Another ferroptosis inducer acting on GPX4, FIN56, was found to induce autophagy in the bladder cancer model, which in turn promoted the degradation of GPX4 and ferritin, thereby accelerating the process of ferroptosis.⁹³ This is expected to help us gain a clearer and more comprehensive understanding of the mechanism of action of such drugs.

In contrast to drugs that affect amino acid and lipid metabolism, certain iron-containing regulators, such as heme,⁹⁴ ferric ammonium citrate,⁹⁵ and ferrous chloride,⁹⁶ can disrupt the intracellular iron metabolism balance through iron input, intensify LPO, and promote ferroptosis. Conversely, regulators such as dihydroartemisinin (DHA),⁹⁷ polyphyllin (PPI),⁹⁸ and salidroside (Sal)⁹⁹ have been proven to induce ferroptosis by triggering intracellular ferritinophagy, which subsequently disrupts the balance of iron metabolism.

In addition to modulating the classical ferroptosis pathway mentioned above, traditional ferroptosis inducers such as Erastin and RSL3 have been shown to enhance the therapeutic effects of chemotherapeutic agents such as Adriamycin and Cisplatin in acute myeloid leukemia, prostate cancer, and other tumors by synergizing with other programmed cell death modalities or affecting glycolysis, among others.^100,101 The most recent study indicated that Erastin and RSL3 enhanced the sensitivity of Adriamycin and Topotecan in tumor cells that expressed P-glycoprotein and breast cancer resistance protein, and overcame drug resistance.¹⁰² These findings further enrich the mechanism of ferroptosis inducers against drug-resistant tumors and lay the foundation for their clinical transformation into anti-tumor therapy.

3.2. Ferroptosis inhibitors

The negative effects of ferroptosis in diseases such as inflammation, neurodegenerative diseases, and cardiovascular lesions can be somewhat ameliorated with the use of ferroptosis inhibitors. A class of iron chelators such as DFO and deferiprone (DFP), which are common inhibitors of ferroptosis, have been widely practiced in the construction of formulations for the treatment of a variety of disease models, such as myocardial infarction,¹⁰³ PD,⁶⁷ and radiation-induced oral mucositis,¹⁰⁴ due to their ability to limit the substrate of the Fenton reaction by lowering the levels of intracellular iron and effectively attenuating the onset of ferroptosis. Baicalein and baicalin are two different active ingredients extracted from the traditional Chinese medicine Scutellaria baicalensis Georgi; studies have shown that baicalin can trigger ferroptosis by down-regulating FTH1 levels.¹⁰⁵ Interestingly, baicalein, which is similar to baicalin, was found to exert a similar effect on ALOX12 inhibitors in models of AMI, effectively attenuating organ damage resulting from ferroptosis, suggesting an important role for LOX inhibitors in attenuating ferroptosis.¹⁰⁶ Another class of inhibitors is synthetic RTAs, including Ferrostatin-1 (Fer-1) and Liproxstatin-1 (Lip-1). These inhibitors mainly exert their effects by inhibiting the process of LPO through scavenging intracellular ROS. For example, Lip-1 has been found to attenuate the release of certain inflammatory factors, alleviate oxidative stress, and protect mitochondrial function in LPS-induced cognitive dysfunction.¹⁰⁷ Overall, the abundance of ferroptosis inhibitors mentioned above provides more therapeutic means and possibilities for certain diseases driven by ferroptosis.

4. Ferritin and ferroptosis

4.1. Ferritin structure, physiological function, and application

As the major iron storage protein, ferritin has been detected in most living cells and has a highly symmetrical cage-like structure with an outer diameter of 12 nm. The external cage shell consists of 24 heavy chain (21 kDa) and light chain (19 kDa) subunits, which exhibit variations in proportions depending on the organ.^112,113 FTH1 and FTL subunits each serve distinct and specialized functions. FTH1 has ferroxidase activity that catalyzes the conversion of Fe²⁺ to Fe³⁺, whereas FTL has nucleating activity with the ability to promote the conversion of Fe³⁺ to a ferrihydrite-like mineral core.^21,114 The internal 8 nm cavity structure functions as the primary storage site for iron and is capable of storing an average of 2000 iron atoms because iron content varies greatly among different species.¹¹⁵ As previously stated, normal ferritin is involved in the regulation of intracellular iron levels by chelating free iron ions and participating in ferritinophagy. Ferritin's ability to chelate iron prevents the occurrence of ferroptosis triggered by large amounts of ˙OH produced by iron overload via the Fenton reaction. When the cellular iron level is low, ferritin becomes active and functional. FTH1 interacts with the C-terminal domain of NCOA4 via certain specific residues.¹¹⁶ Afterwards, iron-bound ferritin is delivered to the lysosome, where the protein is degraded and iron is released into this acidic environment.¹¹⁷

In addition to its routine involvement in body iron regulation, ferritin exhibits a range of biological functions such as immunomodulation and enzyme-like catalytic activity. According to the findings of related studies, heavy chain ferritin exerts a role in mediating immunosuppression by binding to TIM-2.¹¹⁸ Concurrently, it has been found to possess enzyme-like activities, like ferroxidase, peroxidase, and superoxide dismutase (SOD).^119,120 Notably, serum ferritin levels, a critical indicator of iron levels within the body, are highly correlated with a variety of diseases, such as malignant tumours,¹²¹ iron-deficiency anemia,¹²² PD,¹²³ T2DM,¹²⁴ and Kawasaki disease,¹²⁵ and are expected to be used as a diagnostic or prognostic indicator for multiple diseases. Additionally, elevated levels of mitochondrial ferritin have been demonstrated in ischemia/reperfusion injury.¹²⁶ In another ferroptosis-associated disease, OA, the upregulation of ferritin H- and L-subunits has also been observed in macrophages to reduce bioavailable iron levels.¹²⁷

Due to ferritin's favorable safety profile and low immunogenicity, research utilizing ferritin as an antigen delivery system has advanced steadily since Li et al. reported its modification with HIV-1-derived Tat peptides in 2006.¹²⁸ Over the past decade, multiple studies targeting influenza, Epstein–Barr, and SARS-CoV-2 viruses have progressed into Phase I clinical trials.¹²⁹ Earlier, Houser et al. conducted the first in-human Phase 1 clinical trial targeting influenza viruses to evaluate a novel ferritin (H2HA-Ferritin) nanoparticle influenza vaccine platform.¹³⁰ Results demonstrated that this nanoparticle vaccine is safe, well-tolerated, and shows potential for application as a universal influenza vaccine. Subsequently, in a 2022 study, Joyce et al. further developed and evaluated an adjuvanted SARS-CoV-2 spike ferritin nanoparticle (SpFN) vaccine in non-human primates.¹³¹ Relevant research findings indicate that high-titer antibodies generated by SpFN-mediated immune responses neutralize SARS-CoV-2 and rapidly prevent SARS-CoV-2 infection, representing another significant advancement in ferritin-based vaccine research. However, the development of ferritin vaccines still faces certain challenges, such as particle heterogeneity, improper self-assembly, and accidental immunogenicity caused by bulky protein adapters. In response to the aforementioned circumstances, a novel study constructed a highly stable adaptor tag, the Fagy-tag.¹³² Researchers covalently conjugated the Fagy-tagged glycoprotein domain of the rabies virus to ferritin, thereby developing a rabies vaccine candidate exhibiting favourable stability and immunogenicity. It is believed that with the continuous advancement of technology and research, the development of ferritin vaccines will hold greater potential.

In recent years, ferritin has been extensively utilized in the construction of DDS, molecular imaging, bioassay, and vaccine research and development due to its favorable biocompatibility, safety, ability to target tumor cells with high expression of TfR1, ease of structural modification, and natural loading of iron, etc. (Fig. 4).¹³³ Because of the important role played by ferritin in ferroptosis, DDS have been designed to therapeutically induce ferroptosis based on ferritin as a carrier (Table 3), and the mediation of endogenous ferritinophagy (Table 4) has been gradually increasing, opening new avenues for ferroptosis-associated DDS.

Fig. 4 Ferritin and ferroptosis.

Table 3 A summary of drug delivery systems targeting ferroptosis regulation using ferritin as a carrier

Type	Nanosystem	Main mechanism of ferroptosis	Cell line	Drug delivered	Formulation advantage	Ref.
Ferritin simply delivers iron to regulate ferroptosis	Fn-DOX	Fn iron release promotes ROS via the Fenton reaction.	HT29	Iron, Dox	Tumor-targeting ability, chemotherapy combined with ferroptosis for precise anti-tumor treatment	135
	GOx@Fn	GOx consumes glucose to generate H2O2, and Fn provides the Fenton reaction substrate.	4T1	Fe^2+ ions	Targeting tumors with TfR1 expression and enhancing deep tumor penetration	148
	ES-CO@M-HFn	M-HFn iron core is reduced, releasing Fe^3+ ions.	Pan02	ES-CO, Fe^3+ ions	Amplifying oxidative stress, causing DNA damage, destroying tumor cells, and activating immunotherapy	149
Ferritin co-delivery of ferroptosis inducers	mHFn@RSL3/iFSP1	RSL3 and iFSP inhibit GPX4 and FSP, respectively, silencing the intracellular antioxidant pathway.	CT26, MC38	RSL3, iFSP1	Fn precision targeting, ferroptosis-α-PD-L1 immunotherapy mutual enhancement	136
	BSA@RSL3@Fn	RSL3 inhibits GPX4, and Fn synergistically releases Fe^3+.	MDA-MB-231	RSL3, Fe^3+ ions	Long cycling capacity, targeting TfR1 endocytosis uptake, and high biocompatibility	137
	HFn@Fe/siGPX4	siRNA silences GPX4, iron release induces the Fenton reaction, co-promoting ferroptosis.	MCF-7	siGPX4, Fe^3+ ions	Protecting and improving the loading of siRNA, and enhancing lysosomal escape	138
	NFER	Erastin inhibits the Xc^− system, and rapamycin induces ferritinophagy, promoting ROS accumulation.	4T1	Erastin, rapamycin	Carrier-free nanodrug, good biocompatibility, and high stability	139
Combined multi-physical therapy-mediated ferritin destruction	I@P-ss-FRT	GSH triggers Fe^2+ release from Fn, IONP slow release, increasing iron, and depleting GSH.	MCF-7	Fe^2+ ions	Triple functionality of thermal/ferroptosis/MRI for synergistic photothermal transformation against tumors	141
	FCD	Fn releases iron to generate ˙OH. DHA and Fe^2+ synergistic SPDT generates ROS, depletes GSH, inhibits GPX4 activity, and increases LPO levels.	MCF-7	Ce6, DHA, Fe^3+ ions	Chemotherapy, SDT, and PDT, combined with ferroptosis, for multifunctional inhibition of tumor growth	143
	FGLC	FGLC produces ROS, depletes GSH, and promotes ferroptosis.	4T1	Iron, curcumin	Enhancing tumor penetration, consuming glucose for starvation therapy, and overcoming light penetration limitations	144
	Zn-A4@FRT	Activation of ZPP photosensitizers and the Fenton-like reaction cause LPO, deplete GSH, and down-regulate GPX4.	4T1	Zn-A4	Multiple treatment modalities, including PDT and CDT, for enhanced anti-tumor effects	150
	AE@RBC/Fe NCs	AE inhibits GSTP1, promotes LPO, induces ferroptosis, synergizes with PDT to generate ROS, and iron delivery exacerbates the Fenton reaction.	HSC-3	Fe^3+, AE	Long circulation and tumour targeting ability, ferroptosis with PDT for enhanced efficacy	142
	MFn-PPIX	Ultrasound irradiation of PPIX damages MFn, releasing iron ions and PPIX.	MCF-7	PPIX, Fe3O4	Precise targeting, avoiding systemic iron overload, alleviating hypoxia to enhance the effect of SDT	151
	OsNIR@HFn	Near-infrared irradiation initiates ferroptosis.	MDA-MB-231	OsNIR	Immunotherapy and dual apoptosis-ferroptosis jointly inhibit tumor growth and enhance immune cell infiltration.	152
DDSs involving apoferritin nanocages mitigate ferroptosis	SM@ApoFn	ApoFn chelates free iron ions and inhibits iron-related free radical damage.	Chondrocyte	SM04690	Regulating iron and ECM metabolism and targeting inflammatory chondrocytes	146
	CsA@ApoFn	ApoFn reduces unstable iron pool and lipid peroxides, increases GPX4 expression, and CsA reduces ROS levels.	H9c2	CsA	Good targeting of ischaemic cardiomyocytes, with the ability to block apoptosis and ferroptosis	147
	FNC/Cur	Curcumin scavenges ROS, ApoFn nanocage absorbs excess iron, mitigating ferroptosis.	HK-2	Curcumin	Improving curcumin water solubility problems and enhancing renal targeting ability	153
	CGPG-HFn@MnO2/AS	Astragaloside IV (AS) modulates the SIRT1 signalling pathway, and MnO2 nano-enzyme consumes H2O2 to generate O2.	PC12	AS, MnO2 nano-enzyme	Environmental responsiveness, ROS scavenging, and good neuroprotective effects	154

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Table 4 A summary of drug delivery systems based on endogenous ferritin destruction mediating ferroptosis

Type	Nanosystem	Main mechanism of ferroptosis	Cell line	Drug delivered	Formulation advantage	Ref.
Drug-mediated endogenous ferritinophagy	PUS	SSZ disrupts System Xc^−, depletes GSH, and mediates ferritinophagy to increase labile iron pools.	MCF-7	SSZ	pH-Responsive release inhibiting SSZ hematologic adverse effects, improving hydrophobic drug solubility issues	159
	CSAA/Fe@PPI	PPI-induced ferritinophagy, while AA input and GSH depletion by CYS inhibit GPX4.	Huh-7	PPI, Fe^3+ ions, AA	Improved intrinsic properties of PPIs, good biocompatibility, and tumour-targeting ability	158
	8ArmPEG-SS-AC3ManNAz/DBCO-8ArmPEG-SS-DHA@ RSL3	DHA triggers NCOA4-mediated ferritinophagy and releases iron, synergizing with RSL3 to inhibit GPX4.	4T1	RSL3, DHA	Bioresponsive activation, good safety, specific targeting ability, and autophagy-ferroptosis therapeutic synergy	168
	FPBC@SN	SRF upregulates NCOA4 to induce ferritinophagy, inhibits GSH synthesis to downregulate GPX4.	4T1	SRF, NLG919, Fe^3+ ions	Multiple treatment modalities for tumor progression and metastasis inhibition	169
	FP@SFN	FIN56 consumes GPX4 and CoQ10, and piperlongumine (PPL) increases ROS and triggers ferritinophagy.	A549	FIN56, PPL	Toxicity selectivity, good biosafety, and effective tumor suppression by ferroptosis combined with autophagy	170
	PCG-Fe/DHA	DHA disrupts ferritin synergistic Fe^3+ input, depletes GSH, GPX4 decreases, and LPO accumulates.	4T1	Fe^3+ ions, DHA	Dual drug loading, pH responsiveness, and integrated diagnostic and therapeutic capabilities	171
	ApoE-UMSNs-GOx/SRF	UCNP converts NIR to UV to mediate the photoreduction of Fe^3+ to Fe^2+, and SRF inhibits system Xc^− and up-regulates NCOA4.	G422	GOx, SRF	BBB penetration, targeting GBM capacity, and NIR synergize with the iron regeneration system to enhance ferroptosis	172
	LOx/HRP-aZIF	Cascade reaction of LOx with HRP depletes GSH, and HRP and IAA catalyze ROS generation to promote Fn degradation and LPO via bioorthogonality.	SK-N-BE(2)	LOx, HRP	Natural enzyme-dependent cascade reaction combined with the bioorthogonal catalytic reaction for therapeutic effect	173
Combined multi-physical therapy-mediated ferritin destruction	Ce6-PEG-HKN15	HKN15 targets Fn, and activated Ce6 generates ROS to disrupt Fn, prompting Fe^3+ release.	4T1	Ce6	Ferroptosis-PDT synergy for amplified oxidative stress	160
	HKN15@PLGA-PFH	HKN15 contributes to the peripheral accumulation of Fn, and LIFU-regulated ADV material disrupts Fn to release iron.	HCC	PFH	Enhanced drug sensitivity, Fn targeting, and synergistic ADV effect in combination with LIFU for precise control	161
	MC@MH	HKN22-targeted peptide modification induces MC@MH enrichment around Fn and ^68Ga-PSMA-617 stimulates Ce6 to generate ROS.	PC-3	Ce6	CR-PDT combined with MnO2 degradation synergises ferroptosis for diagnosis and treatment	174
	HMPB-H@M1EV	HKN15 targets Fn, and laser irradiation disrupts Fn, synergising with exogenous iron input.	4T1	HMPB	Ferroptosis, combined with immunotherapy, for enhanced anti-tumour treatment	175
	D@MOs-P	Disulfide bond-mediated GSH depletion and GPX4 inactivation synergize with DHA-induced ROS release, while magnetic hyperthermia triggers ferritinophagy.	4T1	DHA	Minimal side effects and excellent T2-weighted MR imaging property	164
	Lipo-PpIX@Ferumoxytol	Ferumoxytol exogenous iron supplementation, PpIX promotes cellular ferritin-selective autophagy via SDT.	4T1	Ferumoxytol, PpIX	SDT mediates apoptosis and ferroptosis to safely and effectively amplify tumour suppression	162
Regulation of FTH1 affects ferroptosis	AZOSH	siRNA silences FHC expression, H2O2 reacts with Arg to produce NO, depletes GSH, generates ONOO^−, and HMOX1 regulates iron and lipid metabolism.	4T1	siRNA, Arg, ZnO2	Multiple gene-level pathways amplifying ferroptosis, enhancing immunotherapy, and suppressing tumour progression	167
	Fe^0-siRNA NPs	siRNA down-regulates FHC expression, prevents Fe^2+ catalysis and storage, and synergises with Fe^2+ input	HeLa cells	siRNA, Fe^2+ ions	pH-Dependent degradation behavior and lysosomal escape capability	176
	BAI@cLANCs	Baicalin down-regulates FTH1, DHLA degradation converts Fe^3+ to Fe^2+, and DHLA and Baicalin exacerbate H2O2 production.	CT26	Baicalin	Endogenous Fe^2+ enrichment for ferroptosis self-amplification in preparation systems	166
	Ca/Fe nanozyme	Upregulation of FTH1 and GPX4 expression inhibits ferroptosis.	AR42J	—	Regulating ferroptosis, reducing inflammation levels, and alleviating multi-organ damage	177

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4.2. DDS based on ferritin as a carrier targeting ferroptosis therapy

4.2.1. Ferritin simply delivers iron to regulate ferroptosis. Based on the background given above, the exogenous loading and delivery of iron using ferritin as a drug delivery vehicle to disrupt intracellular iron metabolism homeostasis and thus induce ferroptosis in tumor cells via the Fenton reaction has extraordinary advantages.¹³⁴ For example, Yang et al. designed nanoparticles (Fn-DOX) consisting of the anti-tumor chemotherapeutic drug doxorubicin (DOX) and exogenous ferritin, which synergistically and effectively induced ROS accumulation and ferroptosis in the transferrin receptor overexpressing tumor cells HT29 through the co-encapsulation of the chemotherapeutic drug and the exogenous iron within the ferritin nanocages, providing a new option for anti-tumor drug carriers.¹³⁵ The feasibility of iron-induced ferroptosis via loading ferritin as a carrier for anti-tumor therapy was also demonstrated.

4.2.2. Ferritin co-delivery of ferroptosis inducers. Simple iron input has a limited effect on regulating the sensitivity of tumor cells to ferroptosis, making it difficult to meet complex clinical demands. Therefore, many recent studies have begun to focus on the possibility of ferritin as a drug carrier for the co-delivery of iron with ferroptosis inducers and for the dual- or multi-strategy potentiation of intracellular ferroptosis in tumor cells. Cheng et al. utilized ferritin as a carrier to load GPX4 and FSP1 inhibitors, and the dual-pathway synergistic immunotherapy inhibited the intracellular antioxidant pathways, effectively enhancing the efficacy of ferroptosis-based anti-tumor therapy.¹³⁶ The introduction of ferritin endows the formulation with the ability to specifically target TfR1, which is highly expressed in tumor cells and satisfies the requirements for precision drug-targeted delivery. In a similar vein, Xue et al. constructed a nanocomplex based on albumin-ferritin (BSA@RSL3@Fn), where BSA and ferritin respectively endowed the complex with long circulation and highly targeted tumor cell capabilities.¹³⁷ The loading of the ferroptosis inducer RSL3 in the system, in synergy with iron, further enhanced the sensitivity of tumor cells to ferroptosis by modulating the intracellular iron metabolism and lipid metabolism balance.

Unlike the above-mentioned delivery systems for small-molecule ferroptosis inducers, the advent of nucleic acid drugs has led to the proposal of a novel siRNA-based delivery system, HFn@Fe/siGPX4, for inducing ferroptosis.¹³⁸ In the nanosystem, siGPX4 silences the expression of GPX4 through the RNAi mechanism, promoting the process of intracellular LPO. On the one hand, the loaded iron disrupts the intracellular iron metabolism balance, facilitating the occurrence of ferroptosis. On the other hand, the positively charged nanocages significantly increase the loading rate of negatively charged nucleic acid drugs and enhance their lysosomal escape ability. Moreover, the introduction of ferritin not only plays the role of precisely targeting the TfR1 of tumor cells, but also protects the siRNA drug from destruction. The whole system is designed with a dual strategy of multiple perspectives to reflect the brilliant cooperation of ferritin, loaded iron, and siRNA. This approach opens up a new way for the nucleic acid DDS to target ferroptosis.

In contrast to the previously mentioned use of ferritin as a delivery vehicle to load ferroptosis inducers to promote ferroptosis, Li et al. developed a ferritin-involved carrier-free nanomedicine, NFER.¹³⁹ In this design, Erastin acts as an iron ferroptosis inducer to inhibit system Xc⁻ activity and promote LPO, while the loaded rapamycin induces ferritinophagy to release iron in a dual strategy to enhance iron ferroptosis induction. Herein, ferritin does not act as a carrier, but rather “steps into the game” and releases iron through rapamycin-mediated autophagy to address the anti-tumor requirements. This suggests the feasibility of designing a ferroptosis DDS by targeting ferritinophagy and also sets the stage for the induction of endogenous ferritinophagy for the regulation of intracellular ferroptosis levels.

4.2.3. Ferritin synergizes with combination ferroptosis therapies. The combination of multiple treatment modalities is a new trend in disease therapy. Photodynamic therapy (PDT) and photothermal therapy (PTT) are novel treatments that utilize light to kill tumor cells with spatial and temporal precision by generating ROS or providing temperature.¹⁴⁰ The ROS generation during treatment helps to promote the process of intracellular LPO and thus synergistically induces ferroptosis. Consequently, in recent years, with the increase in emerging technologies, the combination of ferritin with light, heat, and sound-triggered therapies for targeting tumor-cell ferroptosis has gained popularity in the field of delivery.

Chen et al. proposed integrated thermal/ferroptosis/magnetic resonance imaging (MRI) nanoparticles (I@P-ss-FRT) (Fig. 5),¹⁴¹ where ferritin, functioning as a photothermal transduction agent and MRI probe, was connected to iron oxide particles coated with polydopamine through disulfide bonding. The conversion of light energy into local thermal energy, facilitated by near-infrared light (NIR), resulted in the destruction of the ferritin structure and the release of a substantial amount of Fe²⁺. This process involves the slow release of iron in the form of iron oxide particles, effectively disrupting the homeostasis of intracellular iron metabolism. Meanwhile, iron production is accompanied by a large amount of GSH depletion, collectively increasing the sensitivity of tumor cells to ferroptosis. The results of this study demonstrated that the designed nanoparticles achieved a breast tumor inhibition rate of 83.46% in vivo, which fully highlights the great promise of ferritin-released iron delivery combined with PTT therapy.

Fig. 5 (A) Schematic of the I@P-ss-FRT structure, functions of ferritin and the PTT-enhanced ferroptosis mechanism. (B) The cellular protein expression of GPX-4 in MCF-7/ADR cells treated with I@P and I@P-ss-FRT (50 μg Fe per mL), measured with or without 808 nm laser irradiation (1.25 W cm⁻² and 5 minutes). (C) The relative levels of GPX-4/β-actin (n = 3). (D) Photographs (left) and weights (right) of the dissected tumors from mice in each group at the end of the experiment (n = 5).¹⁴¹ Adapted with permission. Copyright 2024, the Author(s).

Similar to the design by Chen et al., in another study, Wu et al. decorated ferritin on the surface of the red blood cell membrane (RBC)-coated photosensitizer aloe-rhodopsin (AE) to construct AE@RBC/Fe nanocrystals.¹⁴² The whole system has an excellent ability to long-circulate and target tumor cells, and the encapsulated AE can elevate the level of LPO by inhibiting the activity of glutathione S-transferase P1 (GSTP1). Fe³⁺ released by ferritin simultaneously increases intracellular iron abundance and generates the O₂ essential for PDT treatment by reacting with H₂O₂, thus accelerating the mitochondrial disruption of cancer cells caused by the combination of apoptosis and ferroptosis. This emphasizes that tumor cell killing is effectively achieved through multiple cell death pathways.

Zheng et al. introduced sonodynamic therapy (SDT) into the design of a ferritin-targeted ferroptosis delivery system and constructed a ferritin-based nanosensitizer FCD by encapsulating chlorin e6 (Ce6) with DHA.¹⁴³ Consistent with conventionally designed ferritin-targeted ferroptosis delivery systems, the ferritin nanocage first releases encapsulated Fe³⁺ to influence iron metabolism, and DHA further contributes to ferroptosis by reacting with released GSH-reduced Fe²⁺, synergistically generating a large amount of ROS and depleting GSH by light and ultrasound, effectively driving ferroptosis through the classical GSH-GPX4 pathway. This is a new practice where SDT is combined with PDT in ferritin-targeted ferroptosis, laying the foundation for the subsequent design of more complex ferroptosis delivery systems involving multiple dynamic therapies.

The exogenous PDT, PTT, and SDT mentioned above face obstructions by skin, muscle, bone, and other tissues, which, to some extent, compromise their photothermal conversion and ROS efficiency. To overcome these challenges, Xu et al. from Zhejiang University developed a glucose-driven self-luminescent ferritin nanocage. By targeting the ferritin modified with glucose oxidase (GOx) to the tumor site, it reacts with glucose to release ROS, which activates luminol to emit blue-violet light.¹⁴⁴ Meanwhile, the absorption of light by loaded curcumin further amplifies the production of ROS. Excessive intracellular ROS, on the one hand, destroys the extracellular matrix (ECM) of tumor tissue, promoting deep tissue penetration. On the other hand, ROS-induced rapid GSH depletion and reduction of mitochondrial membrane potential prompted ferroptosis and apoptosis to co-occur, exacerbating the tumor death process. The experimental results showed that the endogenous ferritin luminescent cage inhibited cancer cells by 71.73%, confirming that the effective inhibition of breast cancer cells was achieved through the ROS-mediated, graded multi-step response release.

4.2.4. DDSs involving apoferritin nanocages mitigate ferroptosis. The forms of ferritin mentioned above facilitate ferroptosis in DDSs. Apart from tumors, in most diseases (including neurodegenerative diseases and osteoarthritis), ferroptosis promotes the development of the disease processes, and mitigating ferroptosis has become an effective means of treating, ameliorating, and slowing down the disease process in clinical practice. The apoferritin nanocage, which is ferritin with its iron core removed, retains the advantages of ferritin's properties and its enzyme-like activity that catalyzes and stores intracellular Fe²⁺ ions and attenuates ferroptosis. It has already been validated in MPTP-treated PD model mice, where apoferritin nanocages effectively rescued dopaminergic neurodegeneration due to ferroptosis by attenuating iron deposition.¹⁴⁵ Due to the above properties, Deng et al. counterintuitively and innovatively designed an SM04690-containing apoferritin nanocage (SM04690@ApoFn) to ameliorate osteoarthritis, and the delivered drug SM04690 was able to efficiently promote the metabolism of ECM in chondrocytes (Fig. 6).¹⁴⁶ In addition to targeting the TfR1 up-regulated in inflammatory chondrocytes, apoferritin also plays the role of chelating free iron ions, which effectively reduces intracellular iron concentration, inhibits the damage of iron-associated free radicals, improves the OA microenvironment, and attenuates the cellular damage caused by ferroptosis. In MI/R injury, Qian et al. utilized apoferritin nanocage-loaded Cyclosporine A (CsA) to construct CsA@ApoFn targeting TfR1 highly expressed on ischemic cardiomyocytes.¹⁴⁷ After entering the cells, apoferritin inhibited ferroptosis by up-regulating GPX4 levels and decreasing iron content, while at the same time, the encapsulated drug CsA synergistically affected the mitochondrial membrane potential and reduced the apoptotic process by decreasing the accumulation of ROS, which jointly protected cardiomyocytes. In conclusion, the proposal of apoferritin nanocage chelating ferric ions used to inhibit ferroptosis delivery system bridges the gap in the field of ferritin in inhibiting ferroptosis and opens up new ideas for the subsequent development of ferritin ferroptosis-associated disease delivery systems.

Fig. 6 (A) The SM@ApoFn self-assembly preparation process and intracellular induction of the ferroptosis mechanism. (B) The detection of ferrous ions by FerroOrange staining. (C) The measurement of iron content using the iron assay kit. (D) Detection of reactive oxygen species (ROS) in chondrocytes by IL-1β stimulation. (E) The effects of SM@ApoFn on ACSL4 and GPX4 protein expression in IL-1β-stimulated chondrocytes. (F–H) The effect of IL-1β stimulation on TfR expression in chondrocytes.¹⁴⁶ Adapted with permission. Copyright 2024, Elsevier B.V.

4.3. DDS based on endogenous ferritin destruction mediating ferroptosis

4.3.1. Drug-mediated endogenous ferritinophagy in nanoformulations. Ferritinophagy, a form of selective autophagy that targets intracellular ferritin for degradation, can maintain the homeostasis of intracellular iron levels by promoting the degradation and recycling of stored iron.¹⁵⁵ In 2014, the process of NCOA4-mediated ferritinophagy was first identified by Mancias et al.²⁴ Its primary rate-limiting factor, NCOA4, undergoes dynamic regulation. Under conditions of high intracellular iron, NCOA4 binds to the ubiquitin E3 ligase HERC2, leading to its targeted degradation via the ubiquitin-proteasome system. Conversely, during periods of low intracellular iron, their interaction diminishes, thereby promoting ferritinophagy and maintaining intracellular iron levels.¹⁵⁶ This pathway of inducing ferroptosis by increasing intracellular iron levels through endogenous ferritin degradation effectively avoids the inevitable toxic side effects due to the introduction of exogenous materials. More importantly, due to the tumor's own metabolic needs, the naturally high iron environment in the cell is likely to cause cancer cells to “eat their own bitter fruit”, triggering “iron toxicity”. The feasibility of promoting ferroptosis by inducing ferritinophagy for the treatment of malignant tumors has been demonstrated.¹⁵⁷ Thus, the development of DDSs that target endogenous ferritinophagy to disrupt iron homeostasis and induce ferroptosis is of considerable importance.

Certain drugs, such as DHA and PPI, have been found to participate in ferritinophagy induction and enhance ferroptosis sensitivity. Given the above, Chen et al. proposed a self-assembled ferroptosis nano-amplifier (CSAA/Fe@PPI) composed of chondroitin sulfate (CS), arachidonic acid (AA), cysteamine (CYS), and loaded with PPI and Fe³⁺ (Fig. 7).¹⁵⁸ In particular, the redox-sensitive linker CYS was able to scavenge intracellular GSH and inhibit GPX4 activity, whereas loaded PPIs co-regulated intracellular iron levels by inducing ferritinophagy synergistically with exogenous iron inputs. On the other hand, triggered ROS accumulation with AA supplementation exacerbates lethal LPO in the presence of GPX4 inhibition. The proposed system jointly promotes tumor cell ferroptosis through multi-pathway regulation, demonstrating good biosafety and tumor-targeting ability, paving the way for further development of safe and effective ferroptosis DDSs involving endogenous ferritin.

Fig. 7 (A and B) The preparation process of CSAA/Fe@PPI and the therapeutic mechanism of enhanced tumor ferroptosis. (C) Expression analysis of iron overload-related proteins in Huh7 cells under different group treatments. (D and E) CLSM images of cellular LPO detected by the DCFH-DA (D) and BODIPY-C11 (E) probes after different group treatments. (F) WB analysis of GPX4 expression in Huh7 cells under different treatments.¹⁵⁸ Adapted with permission. Copyright 2025, Elsevier B.V.

In another study, Lim et al. investigated the development of a polymerized phenylboronic acid-modified iron oxide nanocomplex (PUS) to achieve auxiliary induction of ferroptosis by modulating ferritinophagy via sulfasalazine (SSZ) loading.¹⁵⁹ In the study, PUS responsively released SSZ in the acidic environment of tumor lysosomes and accelerated tumor cell ferroptosis, relying on its dual action of depleting GSH and inducing ferritinophagy to release iron. During the process, some iron is released from the degraded iron oxide particles and enters the iron pool, thereby replenishing the raw materials for the Fenton reaction. By combining exogenous iron input with endogenous iron reutilization, this DDS demonstrated significant therapeutic effects in MCF-7 modeling mice, providing additional rationale for anti-tumor delivery systems designed to target endogenous ferritinophagy.

4.3.2. DDS integrating multiple physiotherapy-mediated ferritin destruction. There has been a trend toward the use of ferritin as a carrier in conjunction with photothermal and other multimodal physical therapies. Multiphysical therapies are also emerging in the design of DDSs that mediate the destruction of endogenous ferritin.

In this context, a class of DDSs that utilize ferritin-homing peptides to hijack ferritin was designed. For example, Zhu et al. constructed a novel DDS that induces ferroptosis through the spatiotemporal disruption of ferritin by conjugating the ferritin-homing peptide HKN15 with the photosensitizer Ce6 to obtain ferritin-hijacking nanoparticles (Ce6-PEG-HKN15).¹⁶⁰ Due to the involvement of HKN15, the internalized nanoparticles are first enriched around the ferritin and subsequently carry photosensitizers that generate large amounts of ROS under laser irradiation to destroy ferritin to release iron, activate ferroptosis, and then kill tumor cells. The H₂O₂ produced during the process reacts with iron to form O₂, enhancing PDT while further amplifying oxidative stress. The formulation was developed to effectively disrupt the intracellular antioxidant defense system in tumor cells through PDT in conjunction with ferroptosis, and the therapeutic efficacy was well validated in a mouse 4T1 breast cancer model. The development of materials science enabled Liu et al. to build upon the HKN15 design by introducing the acoustic droplet vaporization (ADV)-responsive material perfluorohexane (PFH) to successfully construct a similar ultrasound (US)-responsive nanoparticle (HKN15@PLGA-PFH).¹⁶¹ This system endowed the formulation with the ability to specifically target ferritin through the modification of poly(lactic-co-glycolic acid) by HKN15. In conjunction with sonodynamic therapy (SDT), ferroptosis is exacerbated by utilizing the US environment to trigger a spatiotemporal ADV effect that disrupts ferritin to prompt iron release and drives LPO in a manner that affects the Fenton reaction to deplete GSH and GPX4. The proposed combination therapy strategy has been shown to ameliorate the resistance problem of the first-line anti-tumor drug sorafenib. Furthermore, it has been observed to broaden the construction of DDSs for homing peptide-involved multimodal therapies targeting endogenous ferritin destruction to induce ferroptosis.

Single RCD induction often has limited therapeutic effects on drug-resistant tumors, making it difficult to achieve satisfactory efficacy. Given the SDT background, a liposomal nanosystem (Lipo-PpIX@Ferumoxytol) has been developed in which ferroptosis synergizes with apoptosis to exert antitumor effects.¹⁶² In the system, ferumoxytol, an iron oxide nanoparticle approved for clinical use in the treatment of iron deficiency anemia, disrupts the intracellular iron metabolism balance through exogenous input. The loaded nanosonosensitizer protoporphyrin IX (PpIX) generates ROS to induce apoptosis and synergistically enhances cellular ferroptosis sensitivity by promoting selective autophagy in concert with iron oxidation under US conditions. The proposed scheme triggers both ferroptosis and apoptosis pathways to significantly amplify tumor suppression, which is expected to address the challenges encountered during drug-resistant tumor therapy through the involvement of dual pathways.

In addition to the PDT and SDT previously referenced, magnetic hyperthermia represents another promising anti-tumor physical therapy modality in which magnetic nanoparticles (MNPs) are injected into tumors and heated by an alternating magnetic field in order to kill the tumors.¹⁶³ Here, Song et al. prepared a magnetic “nano-destructor” (D@MOs-P) with a GSH consumption function by coating MNPs with disulfide bond-bridged mesoporous silica shells and loading DHA.¹⁶⁴ The connected disulfide bonds in the system indirectly inhibit GPX4 activity by a thiol-disulfide exchange reaction with GSH. Magnetic hyperthermia generated by MOs-P then triggers ferritinophagy and disrupts intracellular iron homeostasis. The progressive release of ferrous ions activates DHA, which further generates ROS and exacerbates the disruption of the redox balance. Ultimately, this study demonstrated that ferroptosis induced by the disruption of intracellular dual metabolic homeostasis significantly inhibited tumor growth with relatively few side effects. Magnetic hyperthermia was also demonstrated for the first time to function in triggering ferroptosis by enhancing ferritinophagy. The proposal of this project innovatively provides a new model for the regulation of ferroptosis involving multiple strategies and has certain prospects for clinical translation.

4.3.3. DDS for regulating FTH1 to induce ferroptosis. In contrast to the conventional approaches mentioned above, FTH1, which possesses ferroxidase activity and is an essential component of the ferritin nanocage, has recently emerged as a prominent subject in the domain of drug delivery due to the regulation of its levels to influence ferroptosis. It has been reported that small molecule components such as baicalin and silibinin can act on FTH1 to exert ferroptosis regulation.^105,165 In this context, Chen et al. utilized the baicalin properties to construct a nanocatalyst with Fe²⁺ enrichment capability (BAI@cLANCs).¹⁶⁶ Baicalin affected Fe²⁺ catalysis by inhibiting FTH1 activity throughout the system, while the conversion between cross-linked lipoic acid (cLANC) and dihydrolipoic acid (DHLA) reduced Fe³⁺ to Fe²⁺, increasing the endogenous Fe²⁺ reserve and providing more substrates for the Fenton reaction. Baicalin, in turn, acted together with DHLA to induce H₂O₂ production to exacerbate ferroptosis. In summary, this system was constructed to achieve 87.9% tumor inhibition in CT26 model mice, achieving a precise and effective tumor strike through the self-enrichment of endogenous Fe²⁺.

In addition to conventional small-molecule drugs, the rise of gene-based drugs has pioneered the design of DDSs for FTH1-regulated induction of ferroptosis. A nano non-ferrous-based nanoagent (AZOSH) was designed, and the FHC (FTH1) siRNA loaded in the formulation system silenced FHC expression at the gene level to affect ferritin synthesis, which in turn contributed to the buildup of Fe²⁺-induced ferroptosis.¹⁶⁷ At the same time, arginine (Arg) used in the preparation reacted with H₂O₂ to produce NO, which depleted GSH and generated peroxynitrite (ONOO⁻), exacerbating LPO. The NO produced in the whole system upregulated heme oxygenase 1 (HMOX1) expression, stimulating Fe²⁺ release, and collectively amplifying ferroptosis. Notably, the triggering of ferroptosis remodeled the cellular immunogenicity, enhanced T-cell activation and infiltration, and effectively ameliorated the therapeutic limitations of immunotherapy, which is a novel attempt in the combination therapy of ferroptosis and immunotherapy.

5. Summary and outlook

In summary, ferroptosis, as a mode of programmed cell death typically characterized by iron overload, GSH depletion, and GPX4 inhibition, involves a variety of metabolic regulations, including iron, lipids, and amino acids. It plays a key role in the pathogenesis and treatment of various diseases, including tumors, neurodegenerative diseases, and ischemia/reperfusion injury. However, the clinical translation and DDS application of the existing ferroptosis-related therapeutics are significantly hindered by challenges such as inadequate targeting and low bioavailability. Ferritin, an essential iron metabolism-associated protein, exerts a substantial effect on the regulation of intracellular iron levels through its involvement in iron transport, storage, and ferritinophagy. Meanwhile, owing to its advantageous properties, including its specific targeting to the highly expressed TfR1 on tumor surfaces, a unique cavity structure, ease of structural modification, and favorable safety, stability, and biocompatibility profiles, ferritin has garnered considerable attention in the realm of drug delivery. The employment of ferritin nanocages as carriers for loading iron, ferroptosis inducers, or in conjunction with photothermal therapy to enhance ferroptosis in tumor treatment exhibits significant potential. More notably, the ferritin subunit FTH1 possesses the enzyme catalytic activity as well as the ability to chelate iron to attenuate the intracellular toxic Fe²⁺ content and limit the development of the Fenton reaction. This highlights the distinct role of the apoferritin nanocage in modulating the progression of ferroptosis, which contrasts sharply with that of ferritin. Furthermore, it expands the paradigm for utilizing ferritin cages as delivery carriers in the treatment of ferroptosis-related diseases. Additionally, this paper has examined the current research landscape concerning DDSs that target endogenous ferritinophagy. It emphasizes the development of an agent system that modulates endogenous ferritin-induced ferroptosis through pharmacological means, combined with multiphysical therapies and regulatory subunits, with the aim of elucidating an alternative drug delivery mechanism involving ferritin in the regulation of ferroptosis. However, given that ferritin entrapment caused by high expression of TfR1 in liver tissues affects its tumor-targeting ability to a certain extent, further structural modifications to enhance the tissue-specific distribution and increase the effective drug loading to solve the current bottlenecks and problems in the ferritin ferroptosis delivery system will provide more possibilities for the ferritin delivery system involved in the regulation of ferroptosis. Emerging technologies addressing the aforementioned challenges have gradually been developed, such as the innovative protease-induced nanocage (PINC) technology proposed by Sheng et al., which effectively enhances the drug loading capacity while simplifying the process of removing surface-bound drugs.¹⁷⁸ Overcoming the limitations of ferritin in loading poorly soluble and pH-unstable drugs while enabling the combination of different ligands on one nanocage will expand its application in drug delivery and vaccine development.¹⁷⁹ Other techniques and approaches, including biomineralization, have demonstrated the potential to reduce ferritin's interception in the liver and improve its targeted delivery capacity.¹⁸⁰ The next phase of research will further combine these emerging technological tools, focusing on ferritin as a carrier and target, and its unique nanozyme activity in the treatment of ferroptosis-related diseases, which is believed to have good prospects and translational potential.

Conflicts of interest

There are no conflicts to declare.

Data availability

No new datasets were generated or analyzed during the preparation of this review. All referenced data and materials are derived from previously published studies, which are appropriately cited in the text and listed in the reference section. Readers seeking access to the original datasets should contact the corresponding authors of the cited publications directly.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 82373810) and the Jiangsu Pharmaceutical Association–Zhiyuan Pharmaceutical Peiying Jin Fund (J2024010).

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