CCN1 upregulation in diabetic wounds suppresses PINK1/Parkin-mediated mitophagy in dermal fibroblasts by regulating HIF-1α protein stability under decompensated hypoxic conditions.

Despite the severe burden of diabetic ulcers, therapeutic progress remains slow, hindered by an incomplete understanding of the role of hypoxia and other critical hyperglycemia-induced pathophysiological changes. In this study, we demonstrated that hyperglycemia-impaired angiogenesis induced wound hypoxia, which compromised dermal fibroblast function. Our in vitro studies indicated that the "decompensated hypoxia" model recapitulated key features of the diabetic wound hypoxic environment. The cellular communication network factor 1 (CCN1) protein, secreted by human dermal fibroblasts (HDFs) is involved in promoting angiogenesis. However, because revascularization failed in diabetic wounds, CCN1 remained persistently upregulated during the remodeling phase. Excessive CCN1 expression was associated with integrin-mediated signaling, increased PHD2 expression, and HIF-1α destabilization in HDFs. This suppression of the HIF-1α-PINK1-mitophagy axis caused mitochondrial dysfunction and cellular senescence. Although reduced mitophagy under decompensated hypoxic conditions may maintain HDF viability, this compromised adaptive response ultimately contributed to cell senescence and impaired collagen remodeling, which delayed healing in diabetic ulcers. Our study elucidated the mechanism linking tissue hypoxia to impaired HDF function and identified CCN1 as a potential therapeutic target for diabetic wound healing.