Transfection of Hypoxia-Inducible Factor-1α in Wound Healing: A Systematic Review.

INTRODUCTION: Hypoxia-inducible factor-1α (HIF-1α) has emerged as a promising target for enhancing wound healing. Here, we conducted a systematic review to evaluate the efficacy of HIF-1α in improving wound healing. METHODS: We included the latest randomized controlled trials, quasi-experimental studies, nonrandomized trials, controlled before-after studies, analytical studies (cohort study, case-control study), and comparative cross-sectional studies. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were followed. We searched the databases, including PubMed, the Cochrane Library (Cochrane Central Register of Controlled Trials-CENTRAL), EMBASE, and Scopus, until March 15, 2025. Seven studies reporting accelerated healing via the local application of HIF-1α in normal and diabetic mice were included. RESULTS: A two- to three-fold increase in the expression of angiogenesis-related genes (vascular endothelial growth factor, Acta2, and Pecam1) and a 10-fold increase in circulating angiogenic cells were observed in the treated wounds. Vessel maturity in HIF-1α treated wounds increased compared with control, across the included studies. Statistical significance was set at P < 0.05 for angiogenesis and vessel maturity. Significant upregulation of HIF-1α, vascular endothelial growth factor, placental growth factor, and platelet-derived growth factor-B messenger RNA levels was observed (P < 0.05). Histological evidence of increased neovascularization with increased endothelial and smooth muscle cell densities compared to the control groups was observed. Combination therapy with HIF-1α plasmid significantly reduced the wound area (P < 0.05). Angiogenesis, tissue perfusion, and cell homing were three times higher in wounds with HIF-1α transfection. HIF-1α-treated flaps showed significantly less necrosis (P < 0.05) than those in the control group. CONCLUSIONS: HIF-1α-treated wounds showed increased wound healing along with improved neovascularization, vessel maturity, tissue perfusion, and cell homing. We suggest that future studies are warranted on HIF-1α's efficacy and safety in clinical trials in revolutionizing the wound healing arena.