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.