Targeting P2X7R Protects the Retina Against High-Altitude Hypoxia via NLRP3-Mediated Pyroptosis Suppression

High-altitude retinopathy (HAR) is a hypoxia-associated retinal disorder whose molecular drivers remain incompletely defined. Here we tested whether purinergic signaling through the P2X7 receptor (P2X7R) amplifies hypoxia-induced retinal damage. In a murine hypobaric hypoxia model, exposure triggered blood-retinal barrier breakdown, retinal edema, and electrophysiological deficits, accompanied by activation of a P2X7R-NLRP3 inflammasome program and induction of pyroptosis-associated effectors. Pharmacological blockade of P2X7R with A740003 (A74) markedly mitigated vascular leakage and structural/functional impairment, while suppressing inflammasome/pyroptosis-related signaling and oxidative stress. In hypoxia-challenged BV2 cell, A74 similarly reduced ROS accumulation, inflammatory activation, and cell injury. Importantly, genetic silencing of P2X7R by siRNA phenocopied the protective effects of A74 by blunting NLRP3/pyroptosis-related responses and dampening pro-inflammatory cytokine output under hypoxia. Together, these results identify P2X7R as a key upstream amplifier of hypoxia-driven inflammatory injury in the retina and nominate P2X7R inhibition as a mechanistically informed intervention strategy for HAR.