Integrating Bioinformatic Prediction and the "Gut Microbiota-Inflammation-Skin Axis" to Decipher the Mechanisms of Quercetin (from Evodia rutaecarpa) in Diabetic Wound Healing

Zhixuan Huang¹Jian Liu¹Xu Zheng²Xinrong Geng³Jinlong Tan¹Yangwen Ai¹Hui Li^1*Dongyue Zhou^1*

• ¹Institute of Traditional Chinese Medicine Health Industry, China Academy of Chinese Medical Sciences, Nanchang, China
• ²The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, China
• ³Chinese Academy of Sciences Yantai Institute of Coastal Zone Research, Yantai, China

Background: Diabetic foot ulcer (DFU) is a serious complication of diabetes with impaired healing. This study focused on the herbal medicine Evodia rutaecarpa as a case to investigate the mechanisms of diabetic wound healing via the "gut microbiota–inflammation–skin axis". We specifically aimed to elucidate the role of its core bioactive flavonoid, quercetin (Que), whose therapeutic potential in this context remains underexplored. Methods: In vitro, the direct interaction between Que and HIF1α was assessed by cellular thermal shift assay, and its functional effect on the HIF1α/VEGF pathway was evaluated in a lipopolysaccharide-induced RAW264.7 cells and HUVECs co-culture system. In vivo, a streptozotocin-induced diabetic rat model with full-thickness dorsal wounds was treated with Que. Wound healing rates, metabolic parameters, systemic inflammation, and gut microbiota composition were analyzed. The causal role of the gut microbiota was further tested using fecal microbiota transplantation from Que-treated donors to diabetic recipient rats, and the biological activity of resulting drug-containing serum was assessed in HUVEC and RAW264.7 cell cultures. Results: Que was identified as a principal active component of E. rutaecarpa with predicted binding affinity for key targets involved in inflammatory and hypoxic responses. In vitro, Que directly bound to and stabilized HIF1α protein and upregulated the expression of both HIF1α and VEGF in This is a provisional file, not the final typeset article HUVECs under inflammatory co-culture conditions. In diabetic rats, Que treatment significantly accelerated wound closure, improved systemic glucose and lipid metabolism, reduced serum levels of TNF-α and IL-1β, and modulated the gut microbiota structure. FMT from Que-treated rats replicated the pro-healing effects, enhancing angiogenesis and collagen deposition in wounds, and reducing tissue inflammation. Consistently, serum derived from the FMT-Que group promoted HUVEC migration and tube formation, and attenuated the pro-inflammatory cytokine expression in RAW264.7 macrophages. Conclusion: This study demonstrated that Que promoted diabetic wound healing by modulating the "gut microbiota–inflammation–skin axis", thereby reducing systemic inflammation and enhancing local angiogenesis.