Mitochondrial mGPDH Modulates Fibroblast Function in Diabetic Wound Healing via the SIRT1–c-Myc–TGF-β1 Axis

Fibroblasts play a pivotal role in wound healing, particularly during the proliferative and remodeling phase, where they migrate to the injury site, proliferate, and synthesize essential extracellular matrix (ECM) components such as collagen and fibronectin (FN). However, fibroblast functionality is compromised because of factors such as vascular dysfunction and oxidative stress in diabetic wounds, leading to chronic inflammation and delayed healing. This study investigates the role of mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH), a key enzyme in energy metabolism, in regulating fibroblast function during diabetic wound healing. We demonstrate that mGPDH is overexpressed in diabetic wounds and in fibroblasts cultured under high-glucose conditions, contributing to impaired ECM repair. Importantly, the inhibition of mGPDH restores fibroblast functionality by enhancing ECM synthesis, increasing the levels of collagen IV and α-smooth muscle actin (α-SMA) proteins, and accelerating wound healing. Mechanistically, mGPDH deficiency activates the SIRT1-c-Myc-TGF-β1 signaling axis, resulting in reduced c-Myc protein stability, alleviation of its inhibitory effects on TGF-β1 signaling, and subsequent activation of ECM synthesis pathways. This study highlights the role of mGPDH in regulating fibroblast migration and ECM secretion, without affecting apoptosis or proliferation, thereby underscoring its selective regulatory role in wound healing. These findings establish mGPDH as a pivotal regulatory node in fibroblast function during diabetic wound healing, providing a foundation for the development of localized therapeutic strategies aimed at restoring fibroblast activity and improving wound healing outcomes in patients with diabetes. ARTICLE HIGHLIGHTS: Mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) is elevated in diabetic wounds; its inhibition enhances extracellular matrix production and wound closure. mGPDH deficiency activates SIRT1, deacetylating c-Myc to boost TGF-β1 and extracellular matrix production synthesis genes. Targeted mGPDH inhibition can restore fibroblast function and accelerate wound healing in diabetes.