Beyond a gatekeeper: the non-classical signaling role of STRA6 in driving endothelial senescence and atherosclerosis

Endothelial cell (EC) senescence is a fundamental driver of atherosclerosis. This review posits that the primary pathogenic role of Stimulated by Retinoic Acid 6 (STRA6) in the endothelium is not its canonical vitamin A transport but its non-classical function as a signaling receptor for its ligand retinol-binding protein 4 (RBP4). In metabolic diseases such as obesity and type 2 diabetes, elevated RBP4 levels engage endothelial STRA6, initiating a signaling cascade independent of retinol nuclear activity. This process begins with STRA6 activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. The signal is then amplified via crosstalk with the NLRP3 inflammasome, promoting the secretion of pro-senescent cytokines like Interleukin-1β (IL-1β) and establishing a senescence-associated secretory phenotype (SASP). This pro-inflammatory microenvironment subsequently triggers a persistent DNA damage response (DDR), leading to p53/p21-mediated cell cycle arrest and establishing the full senescent phenotype. This perspective reframes STRA6 as a key sensor of metabolic stress that converts systemic signals into a local, pro-atherogenic cellular program. The RBP4-STRA6 signaling axis is thereby identified as a novel therapeutic target. Selectively inhibiting this non-classical pathway may provide a new strategy to uncouple metabolic disease from its destructive vascular consequences.