Kif23 Promotes Myocardial Fibrosis by Suppressing Ces1d-Dependent Lipid Metabolism

BACKGROUND: Myocardial infarction (MI)-induced ischemia leads to abnormal ventricular remodeling and cardiac fibrosis, which can ultimately progress to heart failure. Kif23 (kinesin-like protein 23) has been implicated in the progression of various diseases. This study aims to investigate the role of Kif23 in the development of cardiac fibrosis following MI. METHODS: Male C57BL/6J mice received intravenous injections of adeno-associated virus carrying Kif23 shRNA, followed by left anterior descending coronary artery ligation to induce MI. Cardiac function and fibrosis were assessed via echocardiography, histological analysis, and fibrosis marker quantification at 7 and 14 days post-MI. In vitro, adult rat cardiac fibroblasts underwent Kif23 knockdown or overexpression, with subsequent TGF-β1 (Transforming Growth Factor Beta 1) treatment. Proteomic profiling, lipid droplet analysis, and fibrosis/lipid metabolism assessments were performed. RESULTS: Kif23 expression was significantly upregulated in both infarcted myocardium and TGF-β1-stimulated adult rat cardiac fibroblasts. Kif23 knockdown improved cardiac function and attenuated fibrosis post-MI. In vitro, Kif23 silencing suppressed fibroblast proliferation and myofibroblast transdifferentiation, whereas Kif23 overexpression potentiated fibrotic responses. Proteomic profiling identified Ces1d (carboxylesterase 1d) as a key downstream effector upregulated by Kif23 knockdown, concomitant with restored fatty acid β-oxidation. Mechanistically, Kif23 impairs Ces1d-mediated fatty acid β-oxidation via RhoA (Ras Homolog Family Member A)/ROCK1 (Rho-associated protein kinase 1) signaling, driving fibrosis progression. CONCLUSIONS: Our study identifies Kif23 as a novel regulator of post-MI cardiac fibrosis. Mechanistically, Kif23 drives fibroblast proliferation through RhoA activation and exacerbates fibrogenesis by suppressing Ces1d-dependent fatty acid β-oxidation via the RhoA/ROCK1 axis. This metabolic disruption triggers pathological lipid accumulation and myofibroblast transdifferentiation. These findings nominate Kif23 as a promising therapeutic target for antifibrotic interventions.