Tanshinone IIA inhibits choroidal neovascularization and restores outer blood-retinal barrier function in Vldlr...

Age-related macular degeneration (AMD) is a leading cause of vision loss, with its neovascular form (nAMD) primarily treated using anti-VEGF agents; however, therapeutic resistance and nonresponse remain major clinical challenges. Tanshinone IIA (TIIA), a multi-target bioactive compound derived from Salvia miltiorrhiza, has shown potential in retinal disease treatment. In this study, we investigated the therapeutic effects and underlying mechanisms of TIIA on choroidal neovascularization (CNV) using Vldlr knockout (Vldlr^-/-) mice as an nAMD model. TIIA was administered intraperitoneally for 8 weeks, and CNV progression and vascular leakage were evaluated by OCT and FFA, while outer blood-retinal barrier (oBRB) integrity was assessed by immunofluorescence staining. Proteomics analysis combined with western blotting was used to explore the molecular mechanisms. Our results showed that TIIA significantly reduced CNV area and leakage, and restored oBRB integrity by upregulating tight junction proteins ZO-1 and Occludin in the RPE/choroid complex. Mechanistically, TIIA inhibited angiogenesis via suppression of the PLCγ/ERK1/2 signaling pathway. In addition, proteomics analysis revealed enhanced cholesterol efflux, intermediate filament reorganization, and decreased autophagy-related proteins across the retina, RPE/choroid complex, and serum. Collectively, these findings demonstrate that TIIA alleviates nAMD pathology through multi-target mechanisms, including inhibition of angiogenesis, restoration of barrier function, metabolic reprogramming, and modulation of autophagy, highlighting its potential as an alternative therapeutic strategy for nAMD.