Scutellarin Protects Retinal Ganglion Cells in Glaucoma by Targeting the Hsp90aa1-MAPK Pathway to Inhibit Apoptosis.

PURPOSE: Glaucoma, a major cause of irreversible blindness, is characterized by progressive retinal ganglion cells (RGCs) degeneration. Existing treatments can merely delay disease progression, failing to prevent RGC loss or visual field defects. For the management of ophthalmic diseases, Scutellarin (Scu) has demonstrated neuroprotective potential, but its efficacy and mechanisms in glaucoma remain unexplored. This study aims to evaluate the neuroprotective role of Scu in glaucoma and to reveal its underlying mechanisms. METHODS: Cell viability was assessed using CCK-8 and Hoechst 33342/propidium iodide staining. RGC damage and visual function were evaluated via flash visual evoked potential, immunofluorescence and hematoxylin-eosin staining. The potential targets and pathways were identified by network pharmacology, whereas the Scu-target binding affinity was evaluated by molecular docking and cellular thermal shift assay. Expression of key genes was silenced using siRNA, and protein levels were analyzed by Western blotting. RESULTS: Scu significantly mitigated the damage in a glutamate-induced retinal excitotoxicity glaucoma model. Network pharmacology and molecular docking identified Hsp90AA1 as a key target. Kyoto Encyclopedia of Genes and Genomes analysis associated the protective effects of Scu with the MAPK pathway, which was further supported by GO analysis that highlights its role in apoptosis regulation. Overall, Scu was found to mitigate apoptosis by modulating the Hsp90aa1-MAPK pathway, evidenced by the fact that Hsp90aa1 knockdown abolished the protective effects of Scu. CONCLUSIONS: Scu exerts neuroprotective effects in glaucoma by targeting the Hsp90aa1-MAPK pathway, thereby suppressing apoptosis. This offers a potential therapeutic strategy for glaucoma management.