Abstract Body: We have demonstrated previously that macrophage-mediated inflammation is a key regulator of cell phenotype during disease. Macrophage signaling to smooth muscle cells (SMCs) in diseases such as atherosclerosis and restenosis drives the proliferative, synthetic SMC phenotype that contributes to the hallmarks of disease, which is exaggerated in concomitant diabetes. Here, we identify the histone methyltransferase, SETD4, which was significantly increased in aortic SMCs from diabetic mice compared to control (p<0.05). Additionally, using single cell RNA-sequencing and immunofluorescence of human artery plaques, we demonstrated increased SETD4 expression in diseased plaques compared to adjacent wall. Furthermore, siRNA-mediated knockdown of Setd4 in murine SMCs increased SMC-specific gene expression and prevented downregulation of smooth muscle gene expression by pro-inflammatory macrophage supernatant (p<0.05). IL12 and IL23 significantly upregulated Setd4 expression in mouse aortic SMCs (mAoSMCs) and inhibited SMC gene expression, and this repressive effect was abolished by knockdown of Setd4 in mAoSMCs (p<0.05). Using a histone peptide array, we identified SETD4 as an H3K4 methyltransferase, leading to increased H3K4 dimethylation. Mechanistically, we found that SETD4 directly targets the IL12a and Klf4 gene promoters leading to increased expression of these genes, which both inhibit SMC differentiation. Finally, in a murine model of femoral artery wire injury, Setd4^flox/floxMyh11^Cre+ mice with SMC-specific deletion of Setd4 exhibited smaller neointimal areas (p<0.01), smaller media areas (p<0.05), and smaller intima/(intima + media) ratios (p<0.05). In conclusion, here we demonstrate that pro-inflammatory IL12/23 increases SETD4, which directly increases IL23 and KLF4 expression via H3K4 dimethylation, thereby promoting the synthetic SMC phenotype and worse neointima formation after vessel injury. Our findings thus identify SETD4 as a potential novel therapeutic target of pathologic response to vessel injury.