Background <p>Atherosclerosis (AS) remains a major cause of cardiovascular morbidity and mortality worldwide. and Phenotypic switching of vascular smooth muscle cells (VSMCs) from a contractile to a synthetic phenotype is a critical event in atherosclerotic lesion development. Although miR-148b has been implicated in the regulation of VSMC phenotypic switching, its functional role and underlying mechanism in AS-associated VSMC phenotypic switching remain incompletely understood.</p> Methods <p>An in vitro AS-related VSMC model was established by treating T/G HA-VSMCs with oxidized low-density lipoprotein (ox-LDL). Cell proliferation and migration were assessed using CCK-8, EdU incorporation, and Transwell assays. RNA and protein expression levels were determined by qRT-PCR and western blotting, respectively. The targeted relationship between miR-148b and KLF4 was examined using dual-luciferase reporter and RNA immunoprecipitation assays. KLF4 protein stability and ubiquitination were assessed using cycloheximide chase, MG132 treatment, and immunoprecipitation followed by western blotting.</p> Results <p>miR-148b expression was significantly reduced in ox-LDL-treated VSMCs. Overexpression of miR-148b suppressed ox-LDL-induced VSMC proliferation and migration, and restored the expression of contractile phenotype markers, including SM22α and α-SMA. Mechanistically, KLF4 was identified as a downstream target of miR-148b. miR-148b reduced KLF4 expression through 3′-UTR-mediated repression and was associated with enhanced ubiquitination-dependent KLF4 protein degradation. Rescue experiments showed that KLF4 overexpression partially reversed the inhibitory effects of miR-148b on VSMC proliferation, migration, and phenotypic switching.</p> Conclusion <p>miR-148b attenuates ox-LDL-induced VSMC phenotypic switching, at least in part, by downregulating KLF4. These findings suggest that the miR-148b/KLF4 axis may represent a potential regulatory mechanism in AS-associated vascular remodeling .</p>