SUCNR 1 promotes atherosclerosis by inducing endoplasmic reticulum stress mediated ER-mito crosstalk.

Atherosclerosis is a progressive inflammatory disease within the large and medium arteries. SUCNR1(Succinate receptor 1) has been reported to regulate the inflammatory response in cardiovascular diseases, but how it works in atherosclerosis remains unclear. In this study, we observed that SUCNR1 is upregulated in endothelial cells within human atherosclerotic lesions. The deletion of SUCNR1 in vascular endothelial cells can mitigate the progression of atherosclerotic lesions in high-fat diet ApoE mice. The overexpression or activation of SUCNR1 intensified endoplasmic reticulum stress and mitochondria-endoplasmic reticulum interactions. Moreover, SUCNR1 exacerbated mitochondrial injury, mtDNA leakage, and the activation of cGAS-STING signaling. Elevated mitochondrial damage, ER-mitochondrial interactions, and inflammation induced by SUCNR1 activation were blocked by the endoplasmic reticulum stress inhibitor. Collectively, these findings suggest that SUCNR1 promotes atherosclerosis through endoplasmic reticulum stress signaling mediated ER-mitochondrial crosstalk and its downstream cGAS-STING pathway. Our results provide new insights into the mechanism of SUCNR1 in atherosclerosis and inhibiting endoplasmic reticulum stress signaling may provide a promising strategy to prevent and treat atherosclerosis.