Ferroptosis in gut pathophysiology: Molecular mechanisms and microbial regulation of iron metabolism and oxidative stress

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation and oxidative stress, plays a pivotal role in intestinal pathophysiology. As the main site for iron absorption and a crucial barrier against environmental challenges, the intestinal epithelium is particularly vulnerable to oxidative stress and ferroptotic injury caused by iron overload. Emerging evidence highlights a complex interplay between gut microbiota, oxidative stress and ferroptosis, where pathogenic bacteria exacerbate ferroptosis through iron acquisition and oxidative stress induction, while beneficial microorganisms, particularly probiotics, offer protection by enhancing antioxidant defenses and modulating iron homeostasis. This review synthesizes current knowledge on the molecular mechanisms linking ferroptosis to intestinal diseases, with particular emphasis on dysregulated iron metabolism and redox imbalance in mucosal homeostasis. The bidirectional relationship between the gut microbiota and the regulation of ferroptosis is explored, highlighting key molecular mediators and signaling pathways. In addition, emerging therapeutic strategies targeting oxidative stress and ferroptosis are discussed, ranging from traditional iron chelation approaches to innovative interventions. The integration of these concepts offers valuable insights into the pathogenesis of intestinal diseases and suggests novel strategies for therapeutic development.