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However, the underlying metabolic determinants contributing to these defects remain insufficiently understood. In this study, reduced butyrate is identified in HFD-fed mice and their embryos, accompanied by fetal cardiac abnormalities, including ventricular wall thickening, sarcomere elongation, and myofibril disorganization. These abnormalities can be rescued by butyrate supplementation. For in vitro verification in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and organoids, butyrate effectively restores palmitate-induced contractile dysfunction and myofibrillar disarray. Mechanistically, drug affinity-responsive target stability (DARTS) assays and molecular docking analyses identify pleckstrin homology and RhoGEF domain containing G3 (PLEKHG3), which enables actin binding activity, as a direct target of butyrate. Butyrate binding enhances the interaction between PLEKHG3 and F-Actin, thereby promoting contractility and orderly assembly of myofibrils. Conversely, loss-of-function mutation (Q175A) in PLEKHG3 disrupts PLEKHG3\/F-Actin binding and abrogates protective effects of butyrate. Collectively, these findings reveal that butyrate ameliorates obesity-induced embryonic cardiac defects by modulating the PLEKHG3\/F-Actin axis, highlighting its potential as a therapeutic metabolite for mitigating cardiac abnormalities associated with maternal obesity.<\/jats:p>","DOI":"10.1038\/s44319-026-00911-4","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T15:33:32Z","timestamp":1788276812000},"page":"5606-5631","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Butyrate counteracts maternal obesity-induced cardiac defects by promoting PLEKHG3-actin binding"],"prefix":"10.1038","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-3314-6476","authenticated-orcid":false,"given":"Xueyun","family":"Qin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6278-8043","authenticated-orcid":false,"given":"Laihai","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mo","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiting","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyi","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kexin","family":"Zou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanqi","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0099-9980","authenticated-orcid":false,"given":"Guolian","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"key":"911_CR1","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1038\/s41556-020-0479-y","volume":"22","author":"H Bagci","year":"2020","unstructured":"Bagci H, Sriskandarajah N, Robert A, Boulais J, Elkholi IE, Tran V, Lin ZY, Thibault MP, Dub\u00e9 N, Faubert D et al (2020) Author Correction: Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms. 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