An intraocular oxygenated emulsion suppresses retinal fibrosis by inhibiting hypoxia-driven bioenergetic shifts and mesenchymal transformation

Fibrosis drives progressive organ dysfunction, yet targeted therapies remain limited. In the eye, proliferative vitreoretinopathy (PVR) is a blinding fibrotic disease without approved medical treatment. Here, single-cell RNA sequencing of human PVR membranes revealed convergent activation of hypoxia-responsive programs across major cell populations. Using a molecular probe, we directly validated spatial and temporal hypoxia in an open-globe injury model that recapitulates traumatic PVR. Intravitreal delivery of a supersaturated oxygen emulsion (SSOE) preserved retinal function while reducing fibrocellular membrane formation and inflammation. Mechanistically, human PVR cells exhibited metabolic shifts toward glycolysis alongside epithelial-mesenchymal transition (EMT). SSOE corrected cellular hypoxia, preserved mitochondrial integrity, suppressed glycolytic shift, and inhibited EMT in human retinal pigment epithelial cells, while reducing spontaneous contractility in primary human PVR cell cultures. Together, these findings identify hypoxia as a critical driver of retinal fibrosis and support localized intraocular oxygenation as a viable therapeutic strategy for preventing fibrotic vision loss.