In conclusion, our study provides insights into the mechanobiological role of EGFR-MAPK-KLF5 signaling axis in IFSS-induced phenotypic switching of VSMCs, which is implicated in the development of atherosclerosis, targeting KLF5 or its upstream regulator EGFR and MAPK signaling pathway through small molecular drugs or emerging technologies, such as PROTACs holds promise as a therapeutic approach to prevent VSMCs phenotypic switching and ameliorate atherosclerosis. Here, EGFR is linked to atherosclerosis.