Contribution and Regulation of HIF-1α in Testicular Injury Induced by Diabetes Mellitus

Diabetes mellitus, as a metabolic disorder, has received growing attention for its detrimental effects on the male reproductive system (particularly the testes) manifesting as increased oxidative stress, reduced blood perfusion, heightened inflammation, and germ cell apoptosis under hyperglycemic conditions. Hypoxia-inducible factor (HIF)-1α, a pivotal transcription factor in cellular hypoxia responses, plays a crucial role in regulating metabolism, angiogenesis, and apoptosis. Emerging evidence underscores its significant physiological and pathological roles in diabetic testicular injury. This review outlines the structural domains, activation mechanisms, and key target genes of HIF-1α, and further examines its involvement in diabetes-induced oxidative stress, impaired perfusion, endocrine dysregulation, and the imbalance of apoptosis and autophagy in testicular tissue. Notably, HIF-1α exerts protective effects by activating canonical signaling pathways such as phosphoinositide-3 kinase (PI-3K)/protein kinase B (Akt), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), and nuclear factor (NF)-κB, thereby enhancing antioxidant gene expression, promoting angiogenesis, and upregulating anti-apoptotic proteins. Furthermore, HIF-1α may help stabilize androgen levels by preserving Leydig cell function, potentially alleviating diabetes-associated gonadal dysfunction. This review also discusses the feasibility of targeting HIF-1α as a novel therapeutic strategy. In conclusion, a comprehensive understanding of HIF-1α’s mechanistic role in diabetic testicular damage provides valuable insights into the pathogenesis of diabetes-related reproductive disorders and offers new avenues for therapeutic intervention.