Smarce1-dependent modulation of Stat3 signaling governs cardiomyocyte proliferation.

Developmental pathways that govern organ growth during embryogenesis are often reactivated in adult organisms to support tissue regeneration. Despite their profound clinical relevance for cardiac repair, the molecular mechanisms underlying heart growth during development and regeneration remain incompletely understood. Here, we identify Smarce1, a core subunit of the SWI/SNF chromatin-remodeling complex, as a key regulator of cardiomyocyte (CM) proliferation in zebrafish. Using genetically engineered Smarce1 loss-of-function models, we combined heart-specific transcriptomic (RNA-seq, single-cell RNA-seq) and epigenomic (ATAC-seq) profiling to delineate Smarce1-dependent regulatory networks. Smarce1 deficiency enhanced CM proliferative activity by modulating cell cycle dynamics and chromatin accessibility. Integrative analyses revealed that Smarce1 regulates the transcriptional landscape of Stat3 signaling components, thereby linking chromatin remodeling to proliferative signaling. Genetic and pharmacological modulation of Stat3 signaling confirmed its functional contribution to Smarce1-dependent CM proliferation, establishing a conserved Smarce1-Stat3 axis operating during both developmental and adult cardiac growth. Collectively, our findings uncover an epigenetic mechanism by which Smarce1 fine-tunes CM proliferation and identify Smarce1 as a promising target for promoting regenerative CM expansion.