Novel Association of NAV3 with Dilated Cardiomyopathy and its Role in Cardiac Fibrosis

A genome-wide association study (GWAS) identified neuron navigator 3 ( NAV3) as a potential genetic determinant of myocardial recovery in dilated cardiomyopathy (DCM). This study aimed to understand its functional role in cardiac pathophysiology by leveraging omics approaches. Single-cell RNA-seq transcriptomic data from previously published adult human hearts indicates that NAV3 expression is highest in cardiac fibroblasts, suggesting its functional role in these cells. In vitro, stimulation of primary human ventricular cardiac fibroblasts with TGF-β1, induced NAV3 expression in a dose and time-dependent manner. siRNA-mediated knockdown of NAV3 significantly attenuated TGF-β1-induced fibroblast activation, reducing the expression of α-SMA, collagens, and fibronectin. RNA sequencing of NAV3-silenced fibroblasts confirmed by Western blot revealed upregulation of cell cycle regulators and downregulation of profibrotic markers, suggesting that NAV3 facilitates TGF-β1-induced cell cycle arrest and fibroblast-to-myofibroblast transition. Notably, NAV3 silencing did not alter canonical SMAD2/3 phosphorylation, implying a role for NAV3 in modulating non-canonical fibrotic signaling through other pathways. Our findings provide functional and mechanistic insights into NAV3’s novel role in cardiac fibrosis, showing that reduced NAV3 expression attenuates TGF-β1-mediated fibroblast activation by regulating cell cycle signaling. These results support further investigation of NAV3 as a potential modulator of cardiac fibrosis and myocardial recovery in DCM.