Kaempferol promotes flap survival by inhibiting ferroptosis and inflammation through network pharmacology and in vivo experiments

Abstract Skin flap transplantation is a primary method for wound repair; however, postoperative skin flap necrosis remains a significant challenge. Kaempferol, a flavonol abundant in various foods, exhibits diverse pharmacological effects. This study investigated the potential targets of kaempferol for treating skin flap ischemia–reperfusion (I/R) injury through network pharmacology and molecular docking, followed by in vivo validation. Using SwissTargetPredict, PubChem, SymMap V2, and GeneCards databases, 174 potential target proteins of kaempferol were identified. KEGG and GO enrichment analyses, performed using R software, indicated that kaempferol promotes skin flap survival by modulating ferroptosis, TNF‐α, and NF‐κB signalling pathways. Molecular docking demonstrated stable binding between kaempferol and key proteins, including SIRT1 and NRF2. In vivo, a McFarlane skin flap model was established in Sprague–Dawley rats. Kaempferol treatment improved flap survival, enhanced perfusion areas and distal arteriole visualisation, and increased blood flow in the flap. Furthermore, kaempferol reduced neutrophil infiltration, alleviated oxidative stress, improved mitochondrial morphology and function, and inhibited the release of proinflammatory cytokines. Western blot and immunofluorescence analyses confirmed that kaempferol inhibited ferroptosis and inflammation while promoting flap survival. Mechanistically, kaempferol was found to activate SIRT1‐mediated HMGB1/TLR4/NF‐κB and NRF2/SLC7A11/GPX4 pathways, thereby promoting skin flap survival and mitigating I/R injury.