ABSTRACT NUMBER: ESOC2026A1068 RETINOL BINDING PROTEIN 5 MEDIATES THE CAUSAL EFFECT OF SMOKING ON LARGE ARTERY STROKE BY PROMOTING ENDOTHELIAL-SMOOTH MUSCLE DYSFUNCTION

Abstract Background and aims Smoking is a primary risk factor for Large Artery Stroke (LAS), yet the molecular mediators remains elusive. This study sought to identify causal plasma proteins linking smoking to stroke through an integrative approach. Methods We performed a systematic screen of the UK Biobank proteome to identify smoking-associated proteins. A two-step Mendelian randomization (MR) analysis, integrated with pQTL and GIGAstroke data, was used to determine causal mediation, followed by validation in the DECODE database. Experimental validation was conducted using smoking-exposed Sprague-Dawley rats and vascular cell models (HASMCs and HUVECs) under oxidative stress. Results Screening identified 647 smoking-associated proteins, with Retinol-Binding Protein 5 (RBP5) identified as a critical causal mediator of LAS. In vivo, smoking induced systemic and vascular RBP5 upregulation. In HASMCs, RBP5 promoted a phenotypic switch from contractile to synthetic states, accelerating proliferation via cell cycle and ribosomal biogenesis pathways. Conversely, in HUVECs, RBP5 exacerbated endothelial dysfunction, amplified inflammatory signaling (NF-κB/TNF), and impaired DNA repair mechanisms, leading to barrier disruption. Conclusions Our findings identify RBP5 as a novel functional link between smoking and LAS. Unlike RBP4, which primarily promotes macrophage foam cell formation, RBP5 exerts divergent, cell-specific effects that drive vascular remodeling and endothelial collapse. RBP5 represents a promising therapeutic target for mitigating the cerebrovascular consequences of smoking Conflict of interest Qiuyu Lu, Minyu Bai, Xinjie He, Jianmin Liu, Pengfei Yang,Yu Zhou: nothing to disclose