{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T08:04:33Z","timestamp":1793261073407,"version":"4.5.0"},"reference-count":51,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2026,1,16]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Cardiac hypertrophy is accompanied by profound metabolic remodeling, including enhanced glycolysis. Histone lactylation, a posttranslational modification linked to glycolytic activity, has been shown to regulate gene transcription. However, its role in cardiac hypertrophy remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      Histone lactylation was assessed in failing human and mouse hearts. Male mice subjected to transverse aortic constriction were treated with oxamate (an LDHA [lactate dehydrogenase A] inhibitor) or sodium lactate to modulate histone lactylation. Cardiomyocyte-specific\n                      <jats:italic toggle=\"yes\">Ldha<\/jats:italic>\n                      deletion was also evaluated. In vitro, phenylephrine-stimulated neonatal rat ventricular myocytes were used to examine the effects of lactylation inhibition. Potential histone lactylation transferases were identified by coimmunoprecipitation. Promoter-specific histone lactylation was analyzed by Cleavage Under Targets and Tagmentation and ChIP quantitative polymerase chain reaction, and transcriptional regulation was further evaluated by nascent RNA-seq. TGFB2 (transforming growth factor \u03b22) function was investigated using AAV-shRNA knockdown and lentiviral overexpression in combination with pharmacological inhibition of PI3K (phosphoinositide 3-kinase) or AKT (protein kinase B).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Histone lactylation was elevated in failing human and mouse hearts. Reducing lactylation attenuated transverse aortic constriction-induced hypertrophy and fibrosis, preserving cardiac function, whereas increasing lactylation exacerbated pathological remodeling. In vitro, inhibition of lactylation suppressed phenylephrine-induced cardiomyocyte hypertrophy. P300 and GCN5 (general control non-derepressible 5) were identified as candidate lactylation transferases. Cleavage Under Targets and Tagmentation revealed lactate-dependent enrichment of H3K18la (histone H3 lysine 18 lactylation) at the TGFB2 promoter, correlating with increased TGFB2 expression. Cardiac-specific\n                      <jats:italic toggle=\"yes\">Tgfb2<\/jats:italic>\n                      knockdown reversed the prohypertrophic effects of histone lactylation in vivo, while\n                      <jats:italic toggle=\"yes\">Tgfb2<\/jats:italic>\n                      overexpression promoted cardiomyocyte hypertrophy via PI3K\/AKT\/mTOR (mechanistic target of rapamycin) signaling. Pharmacological inhibition of PI3K or AKT attenuated this effect.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Histone lactylation promotes pathological cardiac hypertrophy and heart failure by upregulating TGFB2 and activating PI3K\/AKT\/mTOR signaling. These findings identify histone lactylation as an epigenetic link between metabolic reprogramming and hypertrophic signaling, and suggest it as a potential therapeutic target for pathological cardiac remodeling.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.125.326185","type":"journal-article","created":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T10:00:20Z","timestamp":1765447220000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":20,"title":["Histone Lactylation Promotes Pressure Overload-Induced Cardiac Hypertrophy and Heart Failure by Regulating TGFB2 Expression"],"prefix":"10.1161","volume":"138","author":[{"given":"Miao","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Surgery, Zhejiang Provincial People\u2019s Hospital (M.C., Y.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery (Z.W., P.T., W.L., L.M., H.X.), The First Affiliated Hospital, Zhejiang University School of Medicine."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Ultrasonography (J.L.), The First Affiliated Hospital, Zhejiang University School of Medicine."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Teng","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery (Z.W., P.T., W.L., L.M., H.X.), The First Affiliated Hospital, Zhejiang University School of Medicine."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinze","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, the Fourth Affiliated 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