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Homozygous null mutations in the G3bp1 gene result in embryonic lethality, underscoring its essential role in development. While various post\u2010translational modifications regulate G3BP1 activity, here we first report that G3BP1 undergoes succinylation (Suc) at Lys (K)411 in mouse hearts (corresponding to human K413). G3BP1\u2010Suc level was diminished in Myosin binding protein C3 (Mybpc3) knockout and transverse aortic constriction (TAC) operated mice, which developed heart failure (HF). Site\u2010directed mutagenesis confirmed that the K413R mutation compromised the overall Suc level of G3BP1 in vitro. Mice injected with AAV9\u2010G3BP1 (WT) developed typical phenotypes of dilated cardiomyopathy (DCM) and HF when compared to mice injected with AAV9\u2010Ctrl and \u2010G3BP1 (K411R) mice, suggesting a possible loss of functional effect of de\u2010Suc at K411. Moreover, Homozygous knock\u2010in G3bp1 (K411R) mice exhibited compromised cardiac parameters compared to WT littermates. De novo G3BP1 mutation (p.E411G) from a DCM patient disrupts Suc at K413. Mechanistically, G3BP1 de\u2010Suc at K413 induced Rraga expression and impaired TSC1\/2 and IDE binding, ultimately leading to excessive activation of the PI3K\u2010AKT\u2010mTOR signaling axis. We demonstrate a critical role for G3BP1 Suc at K413 in cardiac function by modulating the PI3K\u2010AKT\u2010mTOR pathway, providing new insights into the non\u2010canonical function of G3BP1 in cardiomyopathy and HF pathogenesis.<\/jats:p>","DOI":"10.1002\/advs.202519856","type":"journal-article","created":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T18:01:21Z","timestamp":1778436081000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["G3BP1 Succinylation at K413 is Critical for Cardiac Function by Modulating PI3K\u2010AKT\u2010mTOR Signal Axis"],"prefix":"10.1002","volume":"13","author":[{"given":"Yuan","family":"Zhang","sequence":"first","affiliation":[{"name":"Shanghai Key Laboratory of Maternal Fetal Medicine Center for Assisted Reproduction Shanghai First Maternity and Infant Hospital Tongji University School of Medicine Shanghai 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