Hypoxia-inducible factor as a master switch in ocular neovascularization: overcoming anti-VEGF resistance and exploring therapeutic prospects

Abstract Hypoxia-inducible factor (HIF) is a key driver of ocular neovascular diseases. We systematically discuss its regulatory mechanisms and pathological roles in diabetic retinopathy (DR), retinopathy of prematurity (ROP), and neovascular age-related macular degeneration (nAMD). Upon integration of diverse upstream stimuli—including hypoxia, hyperglycemia, oxidative stress, and inflammatory signals—HIF orchestrates a downstream effector network that drives aberrant neovascularization, vascular leakage, fibrotic remodeling, and neuroretinal degeneration. Current anti-vascular endothelial growth factor (Anti-VEGF) therapies, which block only a single downstream factor, are constrained by inadequate response and resistance. Therefore, pharmacological targeting of the upstream “master switch” HIF represents a promising strategy for achieving broader therapeutic efficacy. In this review, we summarize HIF-targeted strategies at the molecular, clinical, and emerging therapeutic levels,with a focus on the translational progress of lead candidates such as 32-134D and PX-478. Furthermore, the present review highlights the dual role of HIF in physiological vascular development and pathological neovascularization, emphasizing that precise regulation of timing, cell type and microenvironment is critical for therapeutic success. Finally, the limitations of current HIF-targeted therapies and future directions are discussed. Collectively, these insights may support the development of more precise and effective therapies for ocular neovascular diseases.