Noni (Morinda citrifolia L.) fruit juice induces ferroptosis in gastric cancer cells via the Nrf2/HO-1–GPX4 axis

Abstract

Noni (Morinda citrifolia L.) is a natural dietary therapeutic plant native to the selenium-rich tropical region of Chengmai, Hainan, China. It exhibits anti-tumor, anti-aging, and lipid-lowering properties; however, the precise mechanism by which it inhibits cancer progression remains unclear. This study investigates the mechanism by which noni juice targets ferroptosis in gastric cancer (GC) and analyzes its bioactive components. First, the efficacy of noni juice was evaluated using an in vivo orthotopic gastric cancer model, while its blood-absorbed components were analyzed via UPLC-Q Exactive MS. Second, network pharmacology and target validation were combined to identify the active ingredients, their targets, and associated pathways. Finally, MKN-45 and SNU-216 cell lines were used to explore the mechanisms by which noni juice inhibits cell proliferation, promotes lipid oxidation, and modifies mitochondrial morphology, thereby inducing ferroptosis in vitro. Results showed that noni juice significantly suppressed gastric cancer progression in mice. UPLC-Q Exactive MS analysis identified flavonoids—including apigenin, naringenin, and curcumol—as major blood metabolites. Both in vivo and in vitro experiments demonstrated that noni juice induced lipid peroxidation, leading to ferroptosis. Treatment with ferroptosis inhibitors successfully reversed this effect. Mechanistically, noni juice regulates the GPX4/HO-1 axis to induce ferroptosis. Pharmacological activation leads to the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) into the nucleus. This process increases the accumulation of lipid peroxidation and malondialdehyde induced by noni. Together, these data support that noni fruit juice suppresses gastric cancer progression and is associated with lipid peroxidation-driven ferroptotic injury involving the Nrf2/HO-1–GPX4 axis.