The mechanism of ferroptosis and its related diseases

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TL;DR

This comprehensive review details the molecular mechanisms of ferroptosis, an iron-dependent form of cell death driven by lipid peroxide accumulation, and its involvement in a wide range of human diseases including cancer, ischemia-reperfusion injury, neurodegenerative disorders, and autoimmune conditions. The paper highlights key regulatory pathways such as the system xc-/GSH/GPX4 axis and the FSP1-CoQ10 pathway, and discusses the therapeutic potential of targeting ferroptosis for both inhibiting and promoting cell death in different disease contexts. The clinical significance lies in the emerging possibility of manipulating ferroptosis as a novel therapeutic strategy, though no ferroptosis-targeting compounds have yet been approved for clinical use.

Full summary

5,196 CHARS

**Background:** Ferroptosis is a regulated form of cell death first identified in 2012 by Dr. Brent R. Stockwell, distinct from apoptosis, necrosis, and autophagy. It is characterized by iron-dependent accumulation of lipid peroxides, leading to mitochondrial shrinkage and increased membrane density. The process involves dysregulation of iron metabolism, accumulation of reactive oxygen species (ROS), and oxidation of polyunsaturated fatty acids (PUFAs) in cellular membranes. Ferroptosis has been implicated in numerous physiological and pathological conditions, including development, aging, tumor suppression, immune function, and a wide array of diseases such as cancer, ischemic diseases, neurodegenerative disorders, cardiovascular disease, autoimmune functions, infection, and iron-overload diseases. This review aims to provide a comprehensive overview of the molecular mechanisms, key regulators, and signaling pathways governing ferroptosis, and to discuss its implications for human diseases and potential therapeutic strategies.

**Methods:** This is a narrative review that synthesizes findings from a large body of published research on ferroptosis. The authors describe the core mechanisms of ferroptosis, including iron metabolism, lipid peroxidation, and the roles of key regulatory systems such as the system xc-/GSH/GPX4 axis and the FSP1/CoQ10 pathway. They also discuss other contributing pathways, including the Hippo-YAP pathway, AMPK signaling, and hypoxia pathways. The review then systematically examines the role of ferroptosis in various disease categories: tumors, ischemia-reperfusion (I/R) injury (myocardial, cerebral, hepatic, renal), neurodegenerative diseases (Alzheimer's, Parkinson's, Huntington's, ALS), cardiovascular diseases (myocardial infarction, atherosclerosis, pulmonary hypertension, cardiomyopathy), autoimmune diseases (SLE, rheumatoid arthritis, IBD, multiple sclerosis), infections (bacterial, viral, parasitic), and iron-overload diseases. For each disease category, the authors summarize updated therapeutic targets and compounds that either promote or inhibit ferroptosis, as presented in extensive tables.

**Key Results:** The review presents a vast amount of data on ferroptosis-related targets and compounds across multiple diseases. Key findings include: - **Tumor suppression:** p53 sensitizes tumor cells to ferroptosis by inhibiting SLC7A11 expression. Other tumor suppressors like BAP1 and RB1 are linked to ferroptosis regulation. Many compounds, including wogonin, ponicidin, sorafenib, and salinomycin, have pro-ferroptotic activity in preclinical cancer models. - **Ischemia-reperfusion injury:** Ferroptosis is implicated in I/R injury across multiple organs. For example, in myocardial I/R injury, ALOX15-mediated production of 15-HpETE triggers ferroptosis in cardiac myocytes. In cerebral I/R injury, upregulation of CDGSH iron-sulfur domain 2 alleviates injury via the NRF2/HO-1 pathway. Numerous inhibitors like ferrostatin-1, liproxstatin-1, and various natural compounds show protective effects. - **Neurodegenerative diseases:** Iron accumulation and lipid peroxidation are observed in AD, PD, HD, and ALS. GPX4 depletion in neurons causes rapid paralysis in mice, resembling ALS. Deferiprone reduces iron concentration in the cervical spinal cord of ALS patients. - **Cardiovascular diseases:** Ferroptosis contributes to myocardial infarction, diabetic cardiomyopathy, doxorubicin-induced cardiomyopathy, and other conditions. For instance, FUNDC2 governs doxorubicin-induced ferroptosis and cardiomyopathy in mice. - **Autoimmune diseases:** In SLE, neutrophil ferroptosis is driven by autoantibodies and interferon α, and liproxstatin-1 attenuates lupus in mice. In RA, TNF-α inhibits ferroptosis by upregulating SLC7A11 and GSH biosynthesis. - **Infections:** Pathogens like Pseudomonas aeruginosa and Mycobacterium tuberculosis induce ferroptosis to enhance pathogenicity. Host cells can also use ferroptosis to limit infection, e.g., oxidative degradation of lipids suppresses HCV replication. - **Iron-overload diseases:** Iron overload in chronic liver disease, Friedreich's ataxia, and type 2 diabetes is linked to ferroptosis. Iron chelators and NRF2 inducers show therapeutic potential.

**Clinical Implications:** The review underscores the dual role of ferroptosis in disease: promoting ferroptosis can suppress tumors and limit certain infections, while inhibiting ferroptosis can protect against I/R injury, neurodegeneration, and autoimmune damage. Despite extensive preclinical evidence, no compounds targeting ferroptosis have been approved for clinical use. The authors emphasize the need for further research to elucidate the precise molecular mechanisms, develop safe and effective ferroptosis modulators, and identify specific biomarkers to guide therapy. The recent solving of the erastin-bound xCT-4F2hc complex structure provides a molecular basis for drug development. Future directions include understanding the interplay between ferroptosis and other cell death forms (e.g., cuproptosis), developing multi-target therapies, and translating preclinical findings into clinical applications.