AMPK activation alleviated dextran sulfate sodium‐induced colitis by inhibiting ferroptosis

Objectives Ferroptosis is a newly discovered cell death mode that has been confirmed to occur in the intestinal epithelial cells in ulcerative colitis (UC). In this study we aimed to elucidate the mechanism of ferroptosis and its association with adenosine monophosphate‐activated protein kinase (AMPK) in UC. Methods Gene expression profiles of colonic mucosa (GSE87473) were downloaded. Both human colonic samples and dextran sodium sulfate (DSS)‐induced colitis murine model were used. The molecular markers of ferroptosis were detected using western blot and immunohistochemistry. Symptoms, iron abundance, and lipid peroxidation level of the mouse model were measured to evaluate the role of AMPK activation in ferroptosis. Results Both gene and protein expressions of GPX4 and FTH1 were decreased in UC patients compared with the healthy controls. An increased iron abundance and lipid peroxidation level in colon tissues and damaged mitochondria were found in DSS‐induced colitis. AMPK expression was decreased in UC patients and correlated with FTH1 and GPX4. Activation of AMPK with metformin inhibited ferroptosis in the colon, improved symptoms, and prolonged the lifespan in DSS‐induced colitis mice. Conclusions Ferroptosis can be observed in colonic tissues in UC. AMPK activation inhibits ferroptosis in murine colitis model, which may act as a potential target for the treatment of colitis. We confirmed ferroptosis in ulcerative colitis based on the GEO database, colonic tissue samples of patients with ulcerative colitis, and a murine colitis model. The adenosine monophosphate‐activated protein kinase (AMPK) activator, metformin, inhibits ferroptosis in the colon, improves symptoms, and prolongs the lifespan in the murine model of dextran sodium sulfate (DSS)‐induced colitis. Our results illustrate that AMPK may be an important target for the inhibition of ferroptosis, which provides a potential therapeutic strategy for colitis. Abbreviations: FTH1, ferritin heavy chain; GPX4, glutathione peroxidase 4