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BACKGROUND: Inflammatory bowel disease (IBD) is a chronically relapsing inflammatory disease with severe diarrhea, fatigue and weight loss. α‐Lipoic acid (LA), a well‐known antioxidant, is able to scavenge reactive oxygen species (ROS) and maintain a healthy cellular redox state. However, the role of LA in protecting IBD is still unclear. Hence the aim of this research was to investigate the protective effect of LA on dextran sulfate sodium salt‐induced ulcerative colitis (UC) and its underlying mechanism. RESULTS: Here, our findings showed that LA significantly alleviated UC symptoms and the overproduction of pro‐inflammatory cytokines in UC mice. In addition, LA treatment inhibited intestinal cell apoptosis by regulating the expression levels of p53/caspase‐3 pathway‐related protein in UC mice. Meanwhile, the inhibitory effects of LA on colonic oxidative stress and ferroptosis were revealed. Our study further demonstrated that LA treatment could regulate the Kelch‐like ECH‐associating protein 1 (Keap1)–nuclear factor E2‐related factor 2 (Nrf2) signaling pathway. Interestingly, we confirmed that LA inhibited ferroptosis by attenuating endoplasmic reticulum stress and suppressing apoptosis in erastin‐induced ferroptosis model in vitro. CONCLUSION: Taken together, this study's findings suggest that LA could be considered as a therapeutic agent protecting against IBD. © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]