Ellagic Acid Alleviates Colitis by Inhibiting Ferroptosis via Nrf2/GPX4 Signaling

Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a key driver of intestinal epithelial injury in inflammatory bowel disease (IBD). The Nrf2–GPX4 signaling axis provides a critical defense against ferroptotic damage; however, its therapeutic modulation remains underexplored. Here, we report that ellagic acid (EA), a natural dietary polyphenol, attenuates dextran sulfate sodium (DSS)-induced colitis by suppressing ferroptosis through activation of the Nrf2/GPX4 pathway. EA treatment markedly reduced disease severity, preserved intestinal barrier integrity, and limited immune cell infiltration. Mechanistically, EA restored GPX4 and SLC7A11 expression while decreasing ACSL4 expression and lipid peroxidation in colonic epithelial (Caco-2) and macrophage (RAW264.7) cells. These findings identify EA as a potent ferroptosis inhibitor that acts on both epithelial and immune compartments, underscoring its potential as a natural therapeutic agent for the prevention and treatment of IBD.