STING Facilitates Vascular Calcification via p-STAT1/NLRP3 Signal

Abstract

Vascular calcification is an independent predictor of cardiovascular mortality in patients with chronic kidney disease (CKD), yet no approved treatment exists. The cGAS-STING signaling participates in various cardiovascular diseases. Notably, DNA damage, an important regulator of vascular calcification, activates the cGAS-STING signaling. However, it remains poorly understood whether STING regulates vascular calcification under CKD conditions. In the current study, we showed that the expression of STING was elevated during vascular calcification. STING knockdown or pharmacological inhibition decreased calcium deposits in vascular smooth muscle cells and human arterial rings, while its activation exacerbated calcification. Furthermore, STING knockout mice exhibited reduced aortic calcification. RNA sequencing analysis suggested that the STAT1 signaling pathway may mediate STING-induced vascular calcification. STING knockdown decreased phosphorylated STAT1 (p-STAT1) levels, and inhibition of p-STAT1 mitigated STING-induced calcification in VSMCs and human arterial tissues. Additionally, STING knockdown downregulated NLRP3 expression, and inhibiting NLRP3 further attenuated STING-induced VSMC calcification, indicating STING accelerates vascular calcification via NLRP3 activation. Altogether, our study highlights the STING/p-STAT1/NLRP3 signaling axis as a key mediator in vascular calcification, suggesting that targeting STING may represent a promising therapeutic approach for vascular calcification in CKD patients.