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Ferroptosis, a form of iron-dependent regulated cell death (RCD), is emerging as a critical mechanism in the pathogenesis and progression of sepsis. This review highlights the intricate molecular pathways and hallmark features of ferroptosis, including lipid peroxidation, dysregulation of iron metabolism, and glutathione depletion, which exacerbate sepsis progression and sepsis-associated multi-organ damage. The systemic interactions of ferroptosis with inflammation, innate, and adaptive immunity, and organ injury are elucidated, emphasizing the role ferroptosis plays both in immunity including sepsis-associated immune cell damage/dysfunction, immune dysregulation, and immunosuppression, and in sepsis-associated multi-organ injury such as acute lung injury (ALI), acute kidney injury (AKI), acute hepatic injury (AHI), acute intestinal injury, septic cardiomyopathy, and septic encephalopathy. Therapeutic strategies targeting ferroptosis hold promise for improving sepsis outcomes. Approaches include pharmacological interventions of ferroptosis-associated pathways, nanoparticle-based delivery systems, and combinatorial therapies aimed at preventing immune dysfunction and protecting against multi-organ failure. Nonetheless, challenges remain in translating preclinical findings into clinical application, necessitating further research into ferroptosis-specific regulatory networks. This review underscores the potential of therapeutics targeting ferroptosis as a transformative approach to addressing sepsis, paving the way for innovative and precision-based clinical interventions.
Zhou et al. (Tue,) studied this question.