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Here, we constructed a high\u2010resolution single\u2010cell transcriptomic atlas of human VSD, benchmarking the pathological state against a 7\u201322 week developmental trajectory. Integrating these single\u2010cell profiles with a reference\u2010based spatial transcriptomic map, we deconvolved the distinct molecular signatures of membranous and muscular septal regions. We found that aberrant cardiomyocyte hypertrophy operates alongside a systemic failure in the non\u2010myocyte microenvironment. Crucially, the ECM regulatory network is dysregulated, driven by attenuated endothelial\u2010fibroblast crosstalk and downregulated THBS1\u2010integrin signaling. Supported by in vitro assays, this dysregulation impairs key endothelial\u2010to\u2010mesenchymal transition (EndoMT) programs and transcriptionally suppresses MMP2. Spatial reconstruction confirmed this maturation block compromises both septal regions, indicating a global remodeling arrest that precludes physical closure. Validated by in situ immunofluorescence and a robust correlation between reduced maternal serum MMP2 levels and defect size, our study portrays VSD as a disease driven by microenvironmental insufficiency and arrested remodeling, providing an integrative framework for understanding human cardiac dysmorphogenesis.<\/jats:p>","DOI":"10.1002\/advs.78016","type":"journal-article","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:00:31Z","timestamp":1790532031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Spatiotemporal Single\u2010Cell Atlas Uncovers Dysregulated ECM Dynamics and Septal Remodeling Arrest in Human Ventricular Septal Defects"],"prefix":"10.1002","author":[{"given":"Xiaoyuan","family":"Zhang","sequence":"first","affiliation":[{"name":"Prenatal Diagnosis Center Reproductive Medicine Center Department of Cell Fate and Diseases Jilin Provincial Key Laboratory of Women's Reproductive 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Rare Disease The First Hospital of Jilin University  Changchun Jilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3121-5680","authenticated-orcid":false,"given":"Ruolin","family":"Jia","sequence":"additional","affiliation":[{"name":"Prenatal Diagnosis Center Reproductive Medicine Center the First Hospital of Jilin University  Changchun Jilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziming","family":"Wang","sequence":"additional","affiliation":[{"name":"Prenatal Diagnosis Center Reproductive Medicine Center Department of Cell Fate and Diseases Jilin Provincial Key Laboratory of Women's Reproductive Health Jilin Provincial Clinical Research Center for Birth Defect and Rare Disease The First Hospital of Jilin University  Changchun Jilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayao","family":"Zhao","sequence":"additional","affiliation":[{"name":"Prenatal Diagnosis Center Reproductive Medicine Center Department of Cell Fate and Diseases Jilin Provincial Key Laboratory of Women's Reproductive Health Jilin Provincial Clinical Research Center for Birth Defect and Rare Disease The First Hospital of Jilin University  Changchun Jilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1070-1308","authenticated-orcid":false,"given":"Bohao","family":"Liu","sequence":"additional","affiliation":[{"name":"Prenatal Diagnosis Center Reproductive Medicine Center Department of Cell Fate and Diseases Jilin Provincial Key Laboratory of Women's Reproductive Health Jilin Provincial Clinical Research Center for Birth Defect and Rare Disease The First Hospital of Jilin University  Changchun Jilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiqing","family":"Xiong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Experimental Hematology National Clinical Research Center for 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