Harnessing HIF-1α for Diabetic Wound Healing: From Molecular Insights to Therapeutic Strategies

INTRODUCTION: Diabetes mellitus severely affects the wound healing process because high blood glucose levels impair insulin availability and increase insulin resistance. The major molecular pathways associated with diabetic wound healing, such as VEGF, Wnt/β-catenin, PI3K/AKT, TGF, MAPK, NF-kappa B, and Nrf2, are regulated by hypoxia-inducible factor-1α (HIF-1α). However, HIF- 1α is rapidly degraded through the ubiquitin-proteasome pathway, which limits its therapeutic potential. METHODS: A systematic literature review was conducted using databases such as PubMed, Scopus, Web of Science, and Google Scholar. Relevant articles focusing on the regulation and degradation of HIF-1α, particularly through the Von Hippel-Lindau (VHL) protein and prolyl hydroxylase domain (PHD) enzymes, were selected to address the review objectives. RESULTS: HIF-1α plays a crucial role in modulating inflammation, angiogenesis, and tissue repair during wound healing. Under normoxic conditions, HIF-1α is hydroxylated by PHD enzymes and subsequently recognized by VHL for degradation via the ubiquitin-proteasome pathway. Inhibition of VHL or PHD enzymes can be a potential target to stabilize HIF-1α, thereby promoting wound healing in diabetic preclinical models. DISCUSSION: Targeted stabilization of HIF-1α through inhibition of its degradation pathway represents a promising therapeutic strategy. Several HIF-1α stabilizers currently in clinical trials for anemia and chronic kidney disease demonstrate the feasibility of this approach, although their application in diabetic wound healing requires further investigation. CONCLUSION: Regulation of HIF-1α degradation presents a novel and promising therapeutic approach for managing diabetic wounds. Future studies are needed to translate these findings into effective clinical therapies targeting HIF-1α stabilization in diabetic wound healing.