Fenofibrate Inhibits Subretinal Fibrosis Through Suppressing TGF-β-Smad2/3 signaling and Wnt signaling in Neovascular Age-Related Macular Degeneration

Abstract
Subretinal fibrosis is a common pathological feature that leads to vision loss in neovascular age-related macular degeneration (nAMD). Currently, treatment options for subretinal fibrosis are limited. In this study, we investigated the effects of fenofibrate, a selective peroxisome proliferator-activated receptor alpha (PPARα) agonist, on subretinal fibrosis in nAMD and explored its underlying molecular mechanisms. Increased collagen deposition and elevated expression of fibrotic markers—including vimentin, collagen-1, alpha-smooth muscle actin, and fibronectin—were observed in very low-density lipoprotein receptor (VLDLR) knockout mice, confirming that Vldlr⁻/⁻ mice serve as a valid model for studying subretinal fibrosis. Treatment with fenofibrate significantly reduced collagen deposition and the expression of these fibrotic markers in Vldlr⁻/⁻ mice. Two major fibrotic pathways, TGF-β-Smad2/3 signaling and Wnt signaling, were found to be upregulated in Vldlr⁻/⁻ retinas but were effectively suppressed by fenofibrate. Furthermore, fenofibrate markedly reduced the expression of connective tissue growth factor (CTGF), a downstream effector of both pathways. Müller cells were identified as a major source of CTGF in Vldlr⁻/⁻ retinas. Fenofibrate inhibited Müller cell activation and consequently decreased CTGF production. In cultured Müller cells, fenofibrate also reversed TGF-β2-induced activation of Wnt signaling and CTGF expression. These results suggest that fenofibrate attenuates subretinal fibrosis by inhibiting TGF-β-Smad2/3 and Wnt signaling Wnt agonist 1 pathways and reducing CTGF expression, highlighting its potential as a therapeutic option for treating nAMD-associated subretinal fibrosis.