Maf1 Ameliorates Cardiac Fibrosis by Methylation of the Sfrp2 Promoter Through Dnmt1.

Cardiac fibroblast (CF) differentiation into myofibroblasts is a crucial driver of cardiac fibrosis, leading to myocardial stiffness and eventually impairing heart function. Cardiomyocyte-fibroblast intercellular communication has emerged as a key regulatory way for CF activation and the fibrotic response. However, the molecular mechanisms linking cardiomyocyte secretomes to CF activation within heart failure remain poorly understood. Here, we identified a stress-responsive protein Maf1 in cardiomyocytes as a central regulator of CF activation in both in vivo and in vitro models of cardiac fibrosis. Maf1 overexpression (cardiomyocyte-specific Maf1 overexpression mice, Maf1 cOE) attenuated CF proliferation, ECM protein expression, and myofibroblast differentiation, while Maf1 loss-of-function (Maf1 knockout mice, Maf1-KO) exacerbated cardiac fibrosis. Notably, Maf1 directly suppresses the expression and secretion of Sfrp2 by affecting its promoter DNA methylation through DNA methyltransferase 1 (Dnmt1), which is essential for promoting CF activation and fibrosis. Sfrp2 overexpression or Sfrp2 recombinant protein treatment exacerbates TGFβ1-induced fibrosis, while silencing Dnmt1 reverses the upregulation of Sfrp2 by Maf1. These findings identify Maf1 as a pivotal link between cardiomyocyte secretomes and fibrosis, suggesting it as a potential therapeutic target to mitigate fibrosis and enhance cardiac recovery during heart failure.