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This review integrates current advancements in understanding the molecular mechanisms driving cardiomyocyte proliferation and myocardial repair. Key signaling pathways\u2014including Hippo\/YAP, Wnt\/\u03b2-catenin, NRG1-ErbB, MAPK, and Notch\u2014orchestrate cardiomyocyte dedifferentiation, cell cycle re-entry, and tissue remodeling. Hippo inhibition promotes cardiomyocyte proliferation and cytoskeletal reorganization, while Wnt\/\u03b2-catenin exhibits dual roles depending on developmental context and injury phase. NRG1-ErbB and MAPK\/ERK pathways integrate metabolic reprogramming and paracrine signaling to enhance regeneration. Transcriptional regulators such as Meis1, GATA4, and Tbx20 modulate cell cycle dynamics, while extracellular matrix components (e.g., Agrin, FSTL1, POSTN) and growth factors (PDGF, FGF, VEGF, Ang-1) reshape the regenerative microenvironment. Despite progress, challenges persist in spatiotemporal control of proliferation, interspecies pathophysiological disparities, and therapeutic delivery precision. Emerging technologies\u2014engineered myocardial grafts, transient modified mRNA systems (e.g., SMRTs), and hypoxia-mediated metabolic switching\u2014highlight translational potential. Future strategies demand integration of multi-omics, biomaterials, and combinatorial interventions to bridge mechanistic insights with clinical applications.<\/jats:p>","DOI":"10.1186\/s13619-026-00297-7","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T04:27:17Z","timestamp":1785212837000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Signaling pathways regulating cardiac regeneration"],"prefix":"10.1186","volume":"15","author":[{"given":"Jianan","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minjie","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6088-8887","authenticated-orcid":false,"given":"Yongyu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,28]]},"reference":[{"key":"297_CR1","doi-asserted-by":"publisher","unstructured":"Aballo TJ, Bae J, Paltzer WG, Chapman EA, Salamon RJ, Mann MM, et al. 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