Abstract

Congenital heart disease (CHD) is a leading cause of neonatal morbidity and mortality, whose underlying pathogenesis remains largely unclear, and lacks reliable biomarkers or therapeutic targets for early detection and treatment during pregnancy. In this study, we investigated the role of endogenous peptide ELABELA (ELA) in fetal CHD. Our findings reveal that ELA levels are significantly reduced in human fetal cardiac tissues with CHD. In mouse models, ELA deletion in cardiac progenitor cells disrupted mitochondrial function, directly contributing to cardiac malformations. Mechanistically, ELA deficiency caused mitochondrial swelling by inhibiting the APJ-AKT-BCL2/BAX signaling pathway. Notably, exogenous ELA administration reduced both CHD severity and incidence in mice. Furthermore, plasma ELA levels were markedly down-regulated in human pregnancies with fetal CHD. These findings establish ELA as a crucial regulator of cardiac development and highlight its potential as both a biomarker and therapeutic target for the prevention and management of fetal CHD during gestation.