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

## TL;DR

This paper explores how STRA6, a protein known for vitamin A transport, also acts as a signaling receptor that promotes endothelial aging and atherosclerosis in metabolic diseases.

## Contribution

The paper introduces STRA6's non-classical signaling role in driving endothelial senescence and atherosclerosis.

## Key findings

- STRA6 activates the JAK/STAT pathway when bound to RBP4, independent of retinol.
- RBP4-STRA6 signaling promotes a pro-senescent secretory phenotype via NLRP3 inflammasome crosstalk.
- This pathway leads to DNA damage and cell cycle arrest, contributing to atherosclerosis.

## Abstract

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.