Smooth muscle DDIT4 exacerbates vascular remodeling in atherosclerosis and vascular injury by impairing PDC activity

Restenosis and atherosclerosis remain therapeutic challenges. Vascular smooth muscle cell (VSMC) phenotypic switching is a central driver. DNA damage inducible transcript 4 (DDIT4) is implicated in vascular disease, but its role in restenosis and atherosclerosis is unknown. Here we show that DDIT4 is markedly increased in PDGF-BB- or IL-1β-stimulated dedifferentiated VSMCs and reduced in differentiated VSMCs. DDIT4 is upregulated in VSMCs within neointima and atherosclerotic lesions of mice and humans, correlating with disease progression. DDIT4 overexpression promotes VSMC proliferation and phenotypic switching, whereas knockdown suppresses these effects. AAV9-mediated Ddit4 overexpression exacerbates neointimal hyperplasia in atherosclerosis and vascular injury models, while VSMC-specific Ddit4 deletion attenuates it. DDIT4 binds the pyruvate dehydrogenase complex, destabilizing subunit interactions and impairing activity. Resulting acetyl-CoA decline reduces histone acetylation, especially at contractile gene promoters, diminishing H3K9/H3K27 acetylation and chromatin accessibility, thereby repressing contractile genes. Targeting DDIT4 is a promising therapeutic strategy for restenosis and atherosclerosis. Vascular smooth muscle cell phenotypic switching drives atherosclerosis and restenosis, but key regulators remain unclear. Here, the authors show DDIT4 promotes this switch via pyruvate dehydrogenase complex inhibition, reducing acetyl-CoA and histone acetylation, repressing contractile genes.