FRZB-induced anti-angiogenic effect via Caveolin-1-mediated TGFβ signalling.

Pathological neovascularization and vascular leakage are central drivers of many sight-threatening diseases. While strategies targeting vascular endothelial growth factor (VEGF) have improved clinical outcomes, many patients do not benefit from the treatment, highlighting the need for alternative therapeutic strategies. Two independent vitreous proteomics studies in patients with proliferative diabetic retinopathy (PDR) reveal a significant reduction in Frizzled-related Protein (FRZB), a finding recapitulated in preclinical models of ocular angiogenesis. Here, we show that loss of Frzb exacerbates ocular angiogenesis, whereas therapeutic delivery of Fc-recombinant FRZB or its netrin-related motif (NTR) robustly suppresses and reverses ocular angiogenesis across various preclinical models. Fc-NTR acts additively with Aflibercept, supporting its potential as a combination therapy. Mechanistically, FRZB binds Caveolin-1 (CAV1), inhibits its phosphorylation at Tyr42, promotes retention of the TGFβ receptor ALK5, and enhances Smad2/3 signalling. These findings define FRZB as a potent suppressor of ocular angiogenesis and establish a promising therapeutic avenue.