Galangin enhances skin flap survival by inhibiting ferroptosis via SIRT1-mediated FOXO1 deacetylation.

Abstract

Skin flap necrosis due to ischemia-reperfusion (I/R) injury remains a major obstacle in plastic and reconstructive surgery. Galangin (Gal) is a natural flavonoid with potent antioxidant and anti-inflammatory properties; its effect on ischemic flap necrosis remains unclear. Network pharmacology and molecular docking were used to predict the interaction between Gal and SIRT1. In vitro, human umbilical vein endothelial cells were subjected to oxygen-glucose deprivation/reperfusion to simulate I/R injury, and subsequent assessments of cell viability and ferroptosis were performed. The SIRT1 inhibitor EX527 and the ferroptosis inhibitor Ferrostatin-1 were used to verify the ferroptosis-related mechanisms. In vivo, a modified McFarlane skin flap model was created in rats. Gal-treated groups were compared to a control group to evaluate flap survival, blood perfusion, histological changes, and the expression of key proteins in the SIRT1/FOXO1 pathway. In vitro, Gal protected HUVECs by suppressing ferroptosis. Mechanistically, Gal upregulated SIRT1, promoted FOXO1 deacetylation, increased expression of downstream proteins and inhibited lipid peroxidation. These protective effects were diminished by SIRT1 inhibition. In vivo, Gal treatment significantly increased flap survival area and blood perfusion in a dose-dependent manner. It also suppressed neutrophil infiltration, reduced MDA levels, increased SOD activity, and inhibited pro-inflammatory cytokines and activate anti-ferroptosis proteins. Gal enhances skin flap survival by suppressing ferroptosis, oxidative stress, and inflammation via activation of the SIRT1/FOXO1 pathway.