Androgen deprivation promotes diabetic wound healing in mice through modulation of wound microbiome and immune response

Ziyang Sun¹Rizhong Huang^2,3Jingyi Chen¹Yangyu Song²Zihao Sun⁴Lixiang Zhang²Huaikai Shi⁵Ruoyu Mu²Yiwei Wang²Jinlong Huang⁶Xin Yan^7*Qian Tan^1,7*

• ¹Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, Clinical College, Nanjing University of Chinese Medicine, Nanjing, China
• ²School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
• ³Jiangxi Technology Business Polytechnic, Nanchang, China
• ⁴Business Intelligence & Data Analytics (BIDA) Program, Heinz College, Carnegie Mellon University, Pittsburgh, United States
• ⁵Asbestos and Dust Diseases Research Institute, Concord, Australia
• ⁶Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
• ⁷Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China

Delayed wound healing is a major complication of diabetes, often associated with chronic inflammation and microbial dysbiosis. Although androgens are known to impair wound repair, their role in diabetic wound healing, particularly in regulating the local wound microbiome and associated immune response, remains poorly understood. In this study, we investigated whether androgen deprivation via surgical castration could enhance diabetic wound healing by modulating local microbial communities and inflammation. Using a full-thickness wound model in db/db mice, we found that androgen deprivation significantly accelerated diabetic wound closure and improved histological outcomes without altering blood glucose levels or body weight. These benefits were accompanied by a more favourable local immune microenvironment, characterized by reduced pro-inflammatory factors and enhanced M2 macrophage polarization. 16S rRNA sequencing revealed that castration increased microbial α-diversity and induced lasting shifts in community composition, particularly during the early phase of healing. Notably, Escherichia-Shigella, Rhodococcus, and Ochrobactrum were enriched, while Staphylococcus abundance was reduced. Functional prediction suggested elevated microbial metabolic activity at the wound site post castration, and machine learning analysis identified Escherichia-Shigella as a key genus associated with accelerated healing. These findings suggest that low androgen levels promote diabetic wound repair by attenuating local inflammation while fostering a more diverse and metabolically active microbiota. Our study highlights a novel link among androgens, wound inflammation, and the microbiome, offering insights into new host-directed therapeutic strategies for chronic wound therapy.