Jingying Sun, Jingying Sun, Yuqi Qian, S Chen, Mi Zhou, Yuanyang Yu, Linlin Wang, Xiaozhong Huang, Xiong Chen, C Zhang, Jia Sun, Jia Sun
A central pathophysiological driver of chronic skin wounds in patients with diabetes and other comorbidities is the dysregulation of the local wound microenvironment, characterized by compromised fibroblast functionality, insufficient extracellular matrix synthesis, and sustained inflammatory dysregulation. Previous studies have revealed that melatonin plays an indispensable role in safeguarding skin structural integrity and sustaining cutaneous homeostasis. However, the role of melatonin in chronic skin wounds associated with diabetes remains poorly understood. In this study, utilizing db/db mouse skin trauma models and in vitro cultures of human dermal fibroblasts (HDF) exposed to advanced glycation end products (AGEs), we established that melatonin robustly augmented granulation tissue formation in db/db mouse skin wounds, consequently expediting in vivo wound healing. Concomitantly, melatonin enhanced the wound reparative capacity of AGEs-treated HDF and stimulated fibroblast proliferation through canonical melatonin receptors (MT1/MT2), while abrogating their differentiation into myofibroblasts and mitigating pro-inflammatory responses. Moreover, RNA-sequencing and functional analyses elucidated that the pro-repair effects of melatonin on skin wounds were mechanistically linked to its modulation of tenascin C and interleukin-10. Collectively, this work thus paves the way for the translational application of melatonin in treating diabetic-associated chronic wounds.