Abstract

Congenital heart disease (CHD) is a prevalent birth defect with complex pathogenesis. MicroRNAs (miRNAs) are crucial regulators, yet their specific roles in CHD remain largely unexplored. This study performed miRNA sequencing on serum samples from CHD patients and identified a distinct profile of dysregulated miRNAs. Based on its pronounced and consistent downregulation, miR-194-5p emerged as a prominent candidate for subsequent functional validation. This downregulation was conserved in a valproic acid-induced murine CHD model, observed in both serum and cardiac tissue. Functional in vivo experiments demonstrated that knockdown of miR-194-5p in neonatal mice impaired cardiac function and suppressed cardiomyocyte proliferation. In vitro, miR-194-5p downregulation inhibited the proliferation of primary cardiomyocytes and impaired the cardiomyogenic differentiation of P19 cells, whereas its overexpression enhanced these processes. Mechanistically, bioinformatics analysis identified Fidgetin (Fign) as a direct target of miR-194-5p, confirmed by dual-luciferase reporter assay and Western blot. Crucially, the impaired proliferation and differentiation phenotypes induced by Fign overexpression were effectively rescued by miR-194-5p mimics. In conclusion, our findings revealed a novel pathogenic axis in CHD, whereby miR-194-5p downregulation impairs cardiac development by directly targeting Fign, highlighting its potential as a therapeutic target.