Role of ferroptosis in 2, 4, 6-trinitrobenzenesulfonic acid induced ulcerative colitis: targeting iron metabolism for therapeutic gain.

Ulcerative colitis (UC), a major form of inflammatory bowel disease (IBD), is characterized by chronic inflammation and ulceration of the colonic mucosa. Its etiology is multifactorial, involving genetic, environmental, and immune factors. Recent evidence highlights the crucial role of ferroptosis, an iron-dependent regulated cell death pathway, in UC pathogenesis. Ferroptosis is marked by excessive accumulation of lipid peroxides, reactive oxygen species, and iron overload, all contributing to epithelial injury. The 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model closely mimics human UC and demonstrates elevated free iron, increased malondialdehyde levels, and decreased glutathione peroxidase 4 expression hallmarks of ferroptotic damage. These molecular disturbances lead to oxidative stress, epithelial barrier dysfunction, and sustained inflammation. Importantly, ferroptosis inhibition shows therapeutic potential. Small-molecule inhibitors such as Ferrostatin-1 and Liproxstatin-1 effectively reduce mucosal damage and restore antioxidant balance, while iron chelators like deferoxamine alleviate iron overload and ROS generation. Moreover, natural compounds including curcumin, resveratrol, epigallocatechin-3-gallate, baicalein, and quercetin demonstrate anti-ferroptotic activity by modulating the nuclear factor erythroid 2-related factor 2/Heme oxygenase-1 pathway, enhancing glutathione peroxidase 4 function, and maintaining iron homeostasis. Collectively, these findings establish ferroptosis as a pivotal mechanism in TNBS-induced UC, linking oxidative stress and iron dysregulation to mucosal injury. Targeting ferroptosis offers a promising therapeutic avenue for UC management, though further clinical and translational studies are needed to validate its efficacy and safety.