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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-1\u03b2 (IL-1\u03b2) 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.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1738384","type":"journal-article","created":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T06:33:40Z","timestamp":1771310020000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Beyond a gatekeeper: the non-classical signaling role of STRA6 in driving endothelial senescence and 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