Abstract
Long noncoding RNAs (lncRNAs) have emerged as crucial regulators in cardiac development and congenital heart disease. With advances in high-throughput sequencing, single-cell omics, and epigenetic profiling, accumulating evidence suggests that lncRNAs participate in transcriptional, posttranscriptional, and structural remodeling processes underlying cardiac morphogenesis. This in-depth review summarizes recent progress in elucidating the roles of lncRNAs in heart development and congenital heart disease pathogenesis. Specifically, we discuss how lncRNAs modulate key developmental signaling pathways, including Notch, Wnt/β-catenin, BMP, and TGF-β, through interactions with chromatin modifiers, transcription factors, and microRNAs. Representative cardiac-enriched lncRNAs, such as
Braveheart
,
Fendrr
,
CARMEN
,
H19
,
MALAT1
, and
TBX5-AS1,
are highlighted for their roles in cardiomyocyte lineage commitment, endothelial-to-mesenchymal transition, endocardial–myocardial interactions, and structural morphogenesis. In various congenital heart disease subtypes, including ventricular septal defect, atrial septal defect, tetralogy of Fallot, and hypoplastic left heart syndrome, lncRNAs exhibit disease-specific expression patterns and participate in regulatory networks involving alternative splicing, competing endogenous RNA interactions, and genomic structural variations. Moreover, circulating and exosomal lncRNAs detected in maternal plasma and amniotic fluid have shown promise as candidate biomarkers for prenatal diagnoses. Collectively, these findings reveal that lncRNAs function as multilayered regulators, linking genetic, epigenetic, and environmental factors during cardiac development. A deeper understanding of lncRNA-mediated mechanisms may provide novel molecular targets, biomarkers, and diagnostic strategies for precision prevention and management of newborn infants with congenital heart disease.