Edaravone Attenuates Retinal Ganglion Cell Ferroptosis Induced by Ischemia Reperfusion via Inhibiting the p38 MAPK/ATF3 Signaling Pathway.

Retinal ischemia-reperfusion injury (RIRI) is a critical pathological process underlying multiple blinding ocular diseases, in which ferroptosis plays a pivotal role. Edaravone (EDA), a potent free radical scavenger, has been reported to exert anti-ferroptotic effects; however, its precise mechanisms in RIRI remain unclear. This study aimed to investigate the protective effects of EDA against RIRI-induced ferroptosis in retinal ganglion cells (RGCs) and to elucidate the underlying molecular mechanisms. In vivo, a rat model of acute high intraocular pressure (HIOP) was established, while an oxygen-glucose deprivation/reoxygenation (OGD/R) model in R28 cells was used in vitro. Retinal structure and function were assessed by histological staining and electrophysiological analysis. Ferroptosis-related changes, including iron accumulation, lipid peroxidation, oxidative stress, and key regulatory proteins, were evaluated. Furthermore, an integrative approach combining network pharmacology, molecular docking, and transcriptomic analysis was employed to identify potential targets and pathways, followed by experimental validation. EDA significantly alleviated retinal structural damage and functional impairment induced by HIOP, and suppressed ferroptosis both in vivo and in vitro, as evidenced by reduced iron overload, decreased ROS and MDA levels, increased SOD activity, and restored expression of GPx4 and xCT. Network pharmacology and molecular docking identified MAPK14 as a key target of EDA. Transcriptomic analysis further revealed ATF3 as a critical downstream mediator. Mechanistically, EDA inhibited p38 MAPK phosphorylation and downregulated ATF3 expression. Activation of p38 MAPK by anisomycin reversed the protective effects of EDA, whereas ATF3 knockdown rescued ferroptosis even under p38 MAPK activation, indicating that ATF3 functions downstream of p38 MAPK. Collectively, EDA exerts anti-ferroptotic effects by regulating the p38 MAPK/ATF3 axis and restoring the System Xc⁻/GPx4 pathway. This study demonstrates that EDA attenuates RIRI-induced ferroptosis in RGCs by inhibiting the p38 MAPK/ATF3 signaling pathway, thereby preserving redox homeostasis and retinal function. These findings provide novel insights into the molecular mechanisms of EDA and suggest a potential therapeutic strategy for RIRI-related retinal diseases.