Wang An, Yang Jialong, Deng Jiapeng, Wang Kaitao, Chen Guodong, Lin Dingsheng
Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, The Second School of Medicine, Wenzhou Medical University, Wenzhou, China.
Wound Repair Regen. 2025 Jan-Feb;33(1):e13250. doi: 10.1111/wrr.13250.
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.
皮瓣移植是伤口修复的主要方法；然而，术后皮瓣坏死仍然是一个重大挑战。山奈酚是一种在各种食物中含量丰富的黄酮醇，具有多种药理作用。本研究通过网络药理学和分子对接研究了山奈酚治疗皮瓣缺血再灌注（I/R）损伤的潜在靶点，随后进行体内验证。利用SwissTargetPredict、PubChem、SymMap V2和GeneCards数据库，确定了山奈酚的174个潜在靶蛋白。使用R软件进行的KEGG和GO富集分析表明，山奈酚通过调节铁死亡、TNF-α和NF-κB信号通路促进皮瓣存活。分子对接表明山奈酚与关键蛋白（包括SIRT1和NRF2）之间存在稳定结合。在体内，在Sprague-Dawley大鼠中建立了McFarlane皮瓣模型。山奈酚治疗提高了皮瓣存活率，增加了灌注面积和远端小动脉可视化，并增加了皮瓣中的血流量。此外，山奈酚减少了中性粒细胞浸润，减轻了氧化应激，改善了线粒体形态和功能，并抑制了促炎细胞因子的释放。蛋白质免疫印迹和免疫荧光分析证实，山奈酚抑制铁死亡和炎症，同时促进皮瓣存活。机制上，发现山奈酚激活SIRT1介导的HMGB1/TLR4/NF-κB和NRF2/SLC7A11/GPX4通路，从而促进皮瓣存活并减轻I/R损伤。
