Ferroptosis in Intestinal Diseases: Molecular Mechanisms, Therapeutic Potential, and Future Perspectives.

Abstract

Ferroptosis is an iron-driven, regulated form of cell death characterized by the gradual accumulation of lipid peroxides within the cell membrane. Intestinal diseases, including inflammatory bowel disease (IBD), ischemia-reperfusion injury (IRI), and colorectal cancer (CRC), are becoming increasingly prevalent and pose a significant burden on public health. Emerging evidence suggests that ferroptosis plays a context-dependent role in these conditions: inhibiting ferroptosis in normal intestinal epithelial cells can mitigate tissue damage, whereas inducing ferroptosis in malignant cells serves as a strategy to suppress tumor progression and metastasis. This review systematically integrates the latest insights into the molecular mechanisms regulating ferroptosis, the pathophysiology of various intestinal diseases, and translational therapeutic strategies. We highlight the therapeutic potential of targeting ferroptosis using inducers or inhibitors (often in combination with the gut microbiota, chemotherapy, radiotherapy, immunotherapy, and nanodrug delivery systems). Despite these advances, significant challenges remain, including the lack of standardized detection methods, variability across experimental models, drug-specific limitations, and safety concerns. In the future, the development of clinically relevant biomarkers, precise drug delivery platforms, and robust translational frameworks will be critical to realizing the potential of ferroptosis-targeted therapies. By integrating mechanistic, pathological, and therapeutic perspectives, this review provides a comprehensive roadmap for leveraging ferroptosis to manage intestinal diseases.