Sox10 escalates vascular inflammation by mediating vascular smooth muscle cell transdifferentiation and pyroptosis in neointimal hyperplasia

Vascular smooth muscle cells (VSMCs) can transdifferentiate into macrophage-like cells in the context of sustained inflammatory injury, which drives vascular hyperplasia and atherosclerotic complications. Using single-cell RNA sequencing, we identify that macrophage-like VSMCs are the key cell population in mouse neointimal hyperplasia. Sex-determining region Y (SRY)-related HMG-box gene 10 (Sox10) upregulation is associated with macrophage-like VSMC accumulation and pyroptosis in vitro and in the neointimal hyperplasia of mice. Tumor necrosis factor α (TNF-α)-induced Sox10 lactylation in a phosphorylation-dependent manner by PI3K/AKT signaling drives transcriptional programs of VSMC transdifferentiation, contributing to pyroptosis. The regulator of G protein signaling 5 (RGS5) interacts with AKT and blocks PI3K/AKT signaling and Sox10 phosphorylation at S24. Sox10 silencing mitigates vascular inflammation and forestalls neointimal hyperplasia in RGS5 knockout mice. Collectively, this study shows that Sox10 is a regulator of vascular inflammation and a potential control point in inflammation-related vascular disease. [Display omitted] •Sox10 contributes to macrophage-like VSMC accumulation, sustaining vascular inflammation•PI3K/AKT-activated Sox10 drives the transcriptional program of VSMC transdifferentiation•Phosphorylation-dependent lactylation is required for Sox10 activity•Inhibition of Sox10 by RGS5 via blocking PI3K/AKT signaling mitigates vascular inflammation Xu et al. show that Sox10 promotes the accumulation and pyroptosis of macrophage-like VSMCs and sustains vascular inflammation. Sox10 is activated by lactylation in a phosphorylation-dependent manner, contributing to the transcriptional program of VSMC transdifferentiation. Suppression of Sox10 activation by RGS5 via blocking PI3K/AKT signaling-mediated phosphorylation forestalls neointimal hyperplasia.