Genetic and Experimental Evidence Identifies STMN1 as a Potential Therapeutic Target in Atherosclerosis

Background: STMN1 regulates microtubule dynamics, cytoskeletal remodeling, and cell migration, but its role in atherosclerosis remains unclear. Methods: eQTL-based two-sample Mendelian randomization was used to assess associations between genetically predicted STMN1 expression and coronary or cerebral atherosclerosis. Functional validation was performed in high-cholesterol diet-fed ApoE−/− mice with AAV9-mediated STMN1 knockdown and in ox-LDL-treated mouse aortic smooth muscle cells with siRNA-mediated STMN1 silencing. Virtual screening was conducted to identify candidate STMN1-binding compounds. Results: Higher genetically predicted STMN1 expression was associated with increased risk of both coronary and cerebral atherosclerosis. In vivo, STMN1 knockdown reduced aortic lesion burden, plaque lipid deposition, plaque area, and inflammatory cytokine expression, while increasing collagen content without significantly altering serum lipid levels. In vitro, STMN1 silencing suppressed ox-LDL-induced inflammation, migration, and MMP2/MMP9 expression. R428 was identified as the top-ranked candidate compound. Conclusions: STMN1 may promote atherosclerosis by regulating vascular inflammation, smooth muscle cell migration, and matrix remodeling.