SERPINB2 increases endothelial inflammation through augmented fatty acid oxidation to promote choroidal neovascularization.

Neovascular age-related macular degeneration (nAMD) is the leading cause of vision loss in the elderly population, with choroidal neovascularization (CNV) being its key pathological feature. Endothelial cell (EC) inflammation plays a pivotal role in CNV progression. However, the crucial molecules regulating EC inflammation and the underlying mechanisms remain unclear. In this study, we found that Serine protease inhibitor family B member 2 (SERPINB2) is significantly upregulated in CNV and ECs during inflammation. SERPINB2 depletion by shRNA markedly reduced EC inflammation and neovascularization in a laser-induced CNV model. SERPINB2 knockdown inhibited EC proliferation, migration, and tube formation, as well as the recruitment and transendothelial migration of monocytes. Mechanistically, SERPINB2 depletion reduced the expression of fatty acid oxidation (FAO)-related genes, such as CPT1C, resulting in lipid accumulation and decreased FAO activity in ECs. ETO (an FAO inhibitor) treatment impaired EC functions, whereas supplementation with fatty acid octanoate rescued EC dysfunction caused by SERPINB2 knockdown. Importantly, delivery of AAV-mediated EC-specific shSerpinb2 or ETO treatment markedly inhibited CNV and inflammation in vivo. Collectively, our findings revealed that SERPINB2 promotes CNV by driving EC inflammation through increased FAO. Targeting SERPINB2/FAO may offer a new promising therapeutic strategy for nAMD treatment.