Ferroptosis in Inflammatory Diseases

Ferroptosis is a form of regulated cell death characterised by iron-dependent lipid peroxidation and failure of cellular antioxidant systems. Initially described in cancer models, it has emerged as a key driver of tissue injury and inflammation across a spectrum of diseases. Dysregulated iron metabolism, depletion of glutathione-dependent enzymes and accumulation of lipid hydroperoxides converge to trigger membrane damage and cell demise. In autoimmune disorders such as rheumatoid arthritis and psoriasis, ferroptotic pathways contribute to aberrant cell death in synovium and epidermis, amplifying inflammatory cascades. In infectious contexts, pathogens from bacteria to viruses can manipulate host ferroptosis to their advantage, promoting survival and spread while evading immune responses. Equally, the gut microbiota exerts bidirectional control over ferroptosis, with commensals modulating lipid peroxidation and barrier integrity. The global burden of chronic inflammatory diseases underscores the need for novel interventions; targeting ferroptosis via iron chelators, lipid peroxidation inhibitors or autophagy modulators offers promising therapeutic avenues. A detailed understanding of ferroptotic triggers and protective mechanisms is now informing preclinical efforts to restore tissue homeostasis and attenuate inflammation.

Research from Nature Portfolio

Recent studies have uncovered mechanisms by which Mycobacterium tuberculosis exploits host epigenetic machinery to induce ferroptosis, enhancing bacterial replication and tissue spread. These findings highlight epigenetic drivers as potential targets to restrain pathogen-induced cell death. In models of rheumatoid arthritis, researchers have shown that combining ferroptosis inducers with tumour necrosis factor antagonists selectively eliminates pathogenic synovial fibroblasts, reducing synovial hyperplasia and joint destruction. Single-cell analyses have identified fibroblast subsets with distinct ferroptotic sensitivities, suggesting that precision modulation of cell death pathways could improve outcomes in chronic joint inflammation.

Ferroptosis in Inflammatory Diseases publication trend

The graph below shows the total number of articles in ferroptosis in inflammatory diseases across all publications each year (not limited to Nature Index journals).

Technical terms

Ferroptosis: regulated cell death dependent on iron-driven lipid peroxidation.

Lipid peroxidation: oxidative degradation of membrane lipids leading to cell damage.

Ferritinophagy: selective autophagic degradation of ferritin releasing intracellular iron.

Synovial fibroblasts: connective tissue cells lining joint cavities that contribute to inflammation.

Glutathione peroxidase 4 (GPX4): key enzyme that reduces lipid hydroperoxides to prevent ferroptosis.

References

1. Ferroptosis hijacking by Mycobacterium tuberculosis. Nature Communications (2023).
2. The Hemagglutinin of Influenza A Virus Induces Ferroptosis to Facilitate Viral Replication. Advanced Science (2024).
3. The influence of microbiota on ferroptosis in intestinal diseases. Gut Microbes (2023).
4. TNF antagonist sensitizes synovial fibroblasts to ferroptotic cell death in collagen-induced arthritis mouse models. Nature Communications (2022).
5. Inhibition of keratinocyte ferroptosis suppresses psoriatic inflammation. Cell Death & Disease (2021).
6. Evidence of pyroptosis and ferroptosis extensively involved in autoimmune diseases at the single-cell transcriptome level. Journal of Translational Medicine (2022).
7. Semaphorin 5A suppresses ferroptosis through activation of PI3K-AKT-mTOR signaling in rheumatoid arthritis. Cell Death & Disease (2022).