Galangin Mitigates Alcohol-Induced Intestinal Damage by Suppressing Ferroptosis via the SESN2/KEAP1/NRF2 Pathway in Mice and Caco-2 Cells

The gut is often referred to as the "second brain" and is highly vulnerable to alcohol exposure. Galangin, a flavonoid extracted from traditional medicinal herbs, <i>Alpinia officinarum</i> Hance, has manifested auspicious clinical application potential. This study aims to explore the regulatory effect of galangin on ferroptosis in an alcohol-related intestinal injury model and its underlying mechanism. In vivo, we confirmed that galangin administration could alleviate alcohol-induced iron metabolism dysfunction and ferroptosis and activate the SESN2/KEAP1/NRF2 signaling pathway in mice colon. In vitro, alcohol-caused disruption of iron homeostasis and ferroptosis could also be significantly reduced by galangin. Using specific small interfering RNA targeting SESN2 (Si-SESN2) or the NRF2 inhibitor ML385 significantly abrogated the protective effect of galangin. Molecular docking and Co-IP results further revealed that galangin activates NRF2 nuclear translocation by promoting KEAP1/SESN2 formation as well as KEAP1/NRF2 dissociation. Collectively, galangin suppressed ferroptosis by activating the SESN2/KEAP1/NRF2 pathway in mice and Caco-2 cells.