MELK drives neointimal hyperplasia and atherosclerosis via vascular smooth muscle cell phenotypic transition

Abstract Cardiovascular diseases associated with atherosclerosis and post-injury restenosis remain leading global causes of mortality. Despite therapeutic advancements, effective treatments targeting the phenotypic transition of vascular smooth muscle cells (VSMCs)—a pivotal event in neointimal hyperplasia and atherosclerosis—are still limited. This study identifies Maternal Embryonic Leucine Zipper Kinase (MELK) as a key regulator of VSMC phenotypic transition in both injury-induced neointimal hyperplasia and atherosclerosis. MELK is significantly upregulated in VSMCs in response to pathological stimuli, driven by transcriptional activation through C/EBPβ. Mechanistically, MELK phosphorylates EZH2 at threonine 367, stabilizing it and enhancing H3K27me3 modifications on VSMC contractile genes, thereby promoting VSMC dedifferentiation. SMC-specific knockout of MELK substantially reduces neointimal hyperplasia and atherosclerosis in mouse models. Notably, selective MELK inhibitor OTSSP167 significantly diminishes neointimal hyperplasia without impairing re-endothelialization, a critical process for vascular repair. This study highlights the potential of MELK inhibition as an approach to treating restenosis and atherosclerosis.