Abstract

Atherosclerosis is a chronic and progressive inflammatory disease that can lead to adverse cardiovascular and cerebrovascular events. Phenotypic switching of vascular smooth muscle cells (VSMCs) plays a pivotal role in its development and progression, but the upstream regulatory mechanisms remain incompletely defined. Here, we identify ubiquitin-fold modifier 1 (UFM1), a ubiquitin-like protein, as a critical regulator of VSMCs plasticity and atherogenesis. In VSMCs stimulated with oxidized low-density lipoprotein (ox-LDL), UFM1 overexpression markedly attenuated phenotypic switching, restoring contractile features and suppressing synthetic activation, accompanied by reduced proliferation and migration. In contrast, UFM1 knockdown further exacerbated these phenotypic alterations. In ApoE −/− mice, adeno-associated virus (AAV)-mediated UFM1 overexpression attenuated VSMCs phenotypic transition and Ki67-positive cell proliferation and significantly reduced atherosclerotic plaque burden. Transcriptomic analyses revealed the phosphoinositide 3-kinase (PI3K)–protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) pathways as downstream candidates, and subsequent pharmacological inhibition experiments confirmed that the PI3K–AKT signaling pathway is the primary mediator of the protective effects of UFM1. Mechanistically, UFM1 limited AKT phosphorylation, thereby restraining VSMCs dedifferentiation and lesion development. Collectively, these findings highlight the UFM1–AKT axis as a promising therapeutic target for atherosclerotic cardiovascular disease.