Integrating OLINK Proteomics and Single-Cell Analysis Reveals that DCBLD2 Potentiates VEGFA-Driven Angiogenesis in Retinal Detachment with Choroidal Detachment.

Rhegmatogenous retinal detachment with choroidal detachment (RRDCD) is a severe ophthalmologic condition whose molecular drivers remain unclear. Here, we integrated Olink proteomics of vitreous fluid from RRDCD and RRD patients (n = 20 each) with single-cell protein activity inference to uncover key pathogenic mechanisms. Proteomic analysis identified 110 statistically significant differentially expressed proteins (DEPs) revealing a significant upregulation of pro-inflammatory pathways, including TNF-α/NF-κB signaling in RRDCD. This multimodal analysis pinpointed DCBLD2 and VEGFA as central cooperating regulators. Functional validation in choroidal endothelial cells confirmed that DCBLD2 and VEGFA act synergistically to enhanced cell proliferation, migration, and angiogenic tube formation. Mechanistically, we demonstrate that DCBLD2 potentiates VEGFA-driven effects by increasing VEGFR2 phosphorylation and activating its downstream AKT and ERK1/2 signaling cascades. Our study reveals a novel synergistic axis where DCBLD2 amplifies VEGFA/VEGFR2 signaling to drive the pathological angiogenesis and inflammation characteristic of RRDCD. This work not only deepens our understanding of RRDCD pathogenesis but also establishes DCBLD2 and VEGFA as promising cooperative biomarkers and therapeutic targets for future clinical intervention.