Targeting Bcl3/NF-κB p50 Pathway for Neuroinflammation Attenuation and RGCs Protection in Retinal Ischemia/Reperfusion Injury

Purpose: Retinal ischemia/reperfusion (IR) injury caused by pathologically high intraocular pressure (ph-IOP) induces excessive inflammation, contributing to retinal ganglion cell (RGC) death in glaucoma. Lowering IOP alone is insufficient, highlighting the need for neuroprotective strategies. Resveratrol (RSV) exhibits anti-inflammatory and neuroprotective effects, but its molecular mechanisms remain unclear. This study aims to evaluate RSV's neuroprotective role and underlying mechanisms in retinal IR injury. Methods: Retinal morphology and RGC survival were assessed via immunofluorescence and hematoxylin and eosin (H&E) staining. Retinal function was evaluated using flash visual evoked potential (F-VEP) and flash electroretinogram (F-ERG). Inflammation and microglial activation were analyzed by quantitative real-time PCR (qRT-PCR) and immunohistochemistry. Pyroptosis and apoptosis were examined using Western blotting, TUNEL staining, and electron microscopy. RNA sequencing, qRT-PCR, and Western blotting identified molecular pathways. Results: RSV significantly protected RGCs and preserved retinal function. It reduced inflammation by inhibiting microglial activation and redistribution. Electron microscopy confirmed its protective effects against apoptosis and pyroptosis. Most importantly, we identified the Bcl3/NF-κB p50 pathway as a key target of RSV. Using the Bcl3-NF-κB p50-specific inhibitor JS-6, we validated this pathway's role in reducing neuroinflammation, pyroptosis, and apoptosis. Conclusions: This study provides insights into RSV's molecular mechanisms and identifies new therapeutic targets for glaucoma.