Hypoxia-induced regional heterogeneity in proliferative vitreoretinopathy: implications for targeted therapies

Proliferative vitreoretinopathy (PVR) represents a common and challenging complication leading to blindness following ocular injury. The prevailing view, which guides current drug development efforts, posits that the mesenchymal transition of retinal pigment epithelium (RPE) underlies the pathogenesis of PVR. However, in our study, by employing single-cell sequencing and immunofluorescence staining on surgically excised PVR membranes, we demonstrate that PVR exhibits distinct cytopathological characteristics depending on their retinal location. Specifically, epiretinal PVR predominantly comprises macrophages, whereas subretinal PVR is primarily constituted of PMEL⁺ RPE-derived cells. Both molecular pathological phenotypes are unified by retinal hypoxia following injury, yet they diverge in their downstream hypoxic pathway selection. Targeting HIF1α-regulated glycolysis selectively reduced epiretinal PVR formation, while inhibiting reactive oxygen species production specifically abrogated subretinal PVR. Furthermore, the application of hyperoxia chamber in a mouse model of dispase-induced retinal injury effectively eradicated PVR across all retinal regions and restored retinal morphology. Our findings establish hypoxia-induced regional heterogeneity as a pathological mechanism in PVR progression and advocate for anatomically targeted therapeutic strategies. © 2025 The Pathological Society of Great Britain and Ireland.