Caveolin-1 in atherosclerosis: from endothelial lipoprotein transport to vascular immunometabolic remodeling

Atherosclerosis is initiated by endothelial dysfunction and pathological retention of apolipoprotein B-containing lipoproteins within the arterial intima, yet the molecular mechanisms governing the earliest steps of lipoprotein entry remain incompletely understood. Caveolin-1 (Cav-1), the principal structural component of endothelial caveolae, has emerged as a critical regulator of vascular lipid transport, mechanotransduction, and inflammatory remodeling. However, its diverse and sometimes opposing biological functions have prevented a unified understanding of its role in atherosclerosis. In this review, we integrate recent advances regarding Cav-1-mediated regulation of atherogenesis, focusing on the transition from endothelial lipoprotein transport to vascular immunometabolic remodeling. We first discuss the structural and biochemical properties of caveolae and the scaffolding functions of Cav-1 that organize signaling and transport platforms. We then examine how Cav-1-dependent caveolar transcytosis facilitates receptor-guided low-density lipoprotein (LDL) transport through scavenger receptor class B type 1 (SR-B1), activin receptor-like kinase 1 (ALK1), and the DOCK4-RAC1 trafficking pathway, thereby controlling early lipid deposition in the arterial wall. Furthermore, we summarize how disturbed flow, glycocalyx disruption, and impaired autophagic turnover regulate Cav-1 abundance and localization, linking vascular biomechanics to lipid handling capacity. Importantly, we highlight the cell type- and disease stage-dependent effects of Cav-1. While endothelial Cav-1 promotes atherogenesis by enabling LDL transcytosis, macrophage Cav-1 deficiency may enhance Toll-like receptor 4/nuclear factor-κB/NLRP3 inflammasome activation and inflammatory plaque remodeling. These opposing functions explain the limitations of systemic Cav-1 targeting and emphasize the need for compartment-selective therapeutic strategies. We then assess the human evidence, comprising CAV1 variant associations with coronary artery disease, plaque and circulating Cav-1 measurements, and monogenic loss-of-function syndromes, and we ask whether established cardiovascular drugs, including statins, PCSK9 inhibitors, and SGLT2 inhibitors, modify this axis. We then set out concrete delivery strategies, including ligand-directed nanocarriers and compartment-specific payload design, through which selective modulation could be achieved. By proposing Cav-1 as a molecular interface connecting mechanical stress, lipid trafficking, and immune-metabolic regulation, this review provides a comprehensive framework for understanding atherosclerosis pathogenesis and identifies potential therapeutic opportunities beyond conventional lipid-lowering approaches.