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Despite advances in diagnosis and therapeutics, the molecular mechanisms underlying CHD pathogenesis remain incompletely understood, limiting the development of efficient targeted therapies. Single-cell omics approaches including single-cell RNA sequencing (scRNA-seq) have revolutionized our understanding of cardiac cellular heterogeneity and intercellular signalling. This review synthesizes recent single-cell omics studies in cardiogenesis and CHD, and presents novel insights from an integrated reanalysis to identify potential therapeutic targets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We systematically reviewed single-cell omics studies in human cardiogenesis and CHD (2019\u20132025), then reanalysed the Hill et al. dataset comprising 157,273 nuclei from paediatric patients across five diagnostic categories, including neonatal and infant hypoplastic left heart syndrome (HLHS), tetralogy of Fallot (TOF), dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) with healthy donor controls. We quantified cardiac-specific ligand-receptor interactions to characterize disease-specific intercellular communication networks through pathway enrichment and network topology analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Reanalysis revealed extensive remodelling of cell\u2013cell communication networks across CHD subtypes, each displaying distinct signalling architectures. Neonatal HLHS and TOF demonstrated hyperactivation of metabolic and growth factor pathways with highly centralized endothelial cell (EC) to cardiomyocyte (CM) and cardiac fibroblast (CF) to CM networks. DCM showed selective metabolic enhancement with preserved integration. In contrast, HCM exhibited broad pathway suppression, particularly morphogen signalling, and fragmented connectivity with weakened CF-CM and EC-CM coupling. Infant HLHS represented an intermediate phenotype with suppressed Notch and extracellular matrix signalling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Single-cell omics studies have revealed cellular heterogeneity and disease-specific mechanisms across CHD subtypes. Our network-based reanalysis demonstrates that CHD involves not only transcriptional defects but also profound disruptions in multicellular communication, with each subtype exhibiting distinct signalling architectures. These findings provide a foundation for precision therapeutic strategies tailored to individual CHD subtypes, with future multimodal approaches accelerating clinical translation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13287-026-05015-3","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T11:55:23Z","timestamp":1776340523000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Single-cell omics uncovers novel pathological mechanisms and therapeutic targets for congenital heart diseases: insights from integrated intercellular communication analysis"],"prefix":"10.1186","volume":"17","author":[{"given":"Phuong Thao","family":"Nguyen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Sahara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,16]]},"reference":[{"issue":"2","key":"5015_CR1","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1093\/ije\/dyz009","volume":"48","author":"Y Liu","year":"2019","unstructured":"Liu Y, Chen S, Zuhlke L, Black GC, Choy MK, Li N, et al. 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