RUNX1 promotes cardiac fibrosis and exacerbates myocardial infarction by transcriptionally activating PTN expression.

BACKGROUND: Myocardial fibrosis is a major pathological change following myocardial infarction (MI). Cardiac fibroblast activation is a key driver in the development of myocardial fibrosis. Runt-related transcription factor 1 (RUNX1) is a transcription factor that promotes tissue fibrosis, but the specific downstream effector through which RUNX1 acts in cardiac fibroblasts after MI has not been defined. This study aims to explore the specific mechanisms by which RUNX1 contributes to cardiac fibrosis following MI. METHODS: The Gene Expression Omnibus (GEO) database was analyzed to explore gene expression changes following MI. Based on its significant upregulation, RUNX1 was selected for investigation of its role in post-MI myocardial fibrosis. RESULTS: The GEO database analysis revealed that RUNX1 was significantly upregulated in mice with MI. Compared with the control group, the MI group exhibited marked cardiac dysfunction accompanied by significantly increased RUNX1 expression. Fibroblast-specific RUNX1 knockdown alleviated post-MI cardiac fibrosis, while RUNX1 silencing suppressed fibroblast activation and secretory function. Mechanistically, as a transcription factor, RUNX1 binds to the pleiotrophin (PTN) promoter and transcriptionally upregulates PTN, thereby exerting pro-fibrotic effects. CONCLUSIONS: This study identifies PTN as a transcriptional target of RUNX1 in cardiac fibroblasts and shows that fibroblast-targeted RUNX1 knockdown attenuates post-MI fibrosis in a PTN-dependent manner. The RUNX1-PTN axis represents a candidate node for fibroblast-directed intervention in post-MI remodeling.