Promotion of DFU Wound Healing via BRG1–COL16A1 Axis in Fibroblasts

Diabetic foot ulceration (DFU) imposes major global health burdens due to high morbidity and recurrence rates. Current therapies (debridement and offloading) show limited efficacy, highlighting the need to uncover molecular mechanisms of diabetic wound repair. Multi-omics analyses of DFU and healthy skin identify fibroblast-derived COL16A1 as a wound healing mediator. In vitro, COL16A1 overexpression or knockdown in fibroblasts is employed to assess its regulatory effects on cellular function and collagen secretory capacity. In vivo, localized adenoviral delivery of COL16A1 is administered to evaluate its therapeutic impact on wound closure in diabetic mice. DNA pull-down plus LC-MS/MS, ChIP-qPCR, and luciferase reporter assays are systematically implemented to delineate the upstream regulatory mechanism of COL16A1 expression. Transcriptomic profiling of skin specimens identifies fibroblast-derived COL16A1 as a key regulatory gene in DFU repair. Subsequent in vitro and in vivo experiments demonstrate COL16A1 enhances fibroblast activation and restores normal repair processes in diabetic wounds. Notably, Brahma-related gene 1 (BRG1) is identified as the key transcription factor governing COL16A1 expression. BRG1 directly binds to the COL16A1 promoter, upregulating its transcription and thereby accelerating diabetic wound healing. BRG1-COL16A1 axis is a critical regulatory pathway and proposes novel therapeutic targets for chronic diabetic wounds.