Glypican-1 modulates TGF-β signaling to drive subretinal fibrosis through a non-canonical AKT-Cyclin A2 cell cycle axis and its inhibition alleviates fibrosis progression

ABSTRACT: Subretinal fibrosis (SRF) is a major cause of irreversible vision loss in neovascular age-related macular degeneration (nAMD) and remains poorly responsive to current anti-vascular endothelial growth factor (anti-VEGF) therapies, with effective therapeutic targets still lacking. Here, using unbiased proteomic profiling of aqueous humor samples from patients with nAMD together with transcriptomic analysis of human choroidal neovascular membranes, we performed cross-omics integration and identified glypican-1 (GPC1) as the only overlapping candidate that was markedly elevated in the aqueous humor of patients with SRF. ELISA validation confirmed significantly increased GPC1 levels in the aqueous humor of patients with SRF, and experimental analyses localized GPC1 expression to retinal pigment epithelial (RPE) cells in vivo. GPC1 expression was markedly upregulated in fibrosis-induced human retinal pigment epithelial cells (ARPE-19) and in mouse models of SRF. Gain- and loss-of-function studies demonstrated that GPC1 promotes fibrotic responses in vitro and in vivo. Mechanistically, GPC1 amplified transforming growth factor-β (TGF-β)-driven fibrotic activation through a non-canonical AKT–Cyclin A2 (CCNA2)-mediated cell cycle axis, thereby enhancing the proliferative and migratory capacities of RPE cells. Importantly, intravitreal administration of a GPC1-neutralizing antibody attenuated SRF in vivo. Collectively, these findings provide mechanistic insight into SRF pathogenesis and support the translational potential of targeting GPC1 to mitigate fibrosis-associated vision loss in nAMD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE325539 | GEO | 2026/09/01

REPOSITORIES: GEO