Histone Lactylation Promotes Pressure Overload-Induced Cardiac Hypertrophy and Heart Failure by Regulating TGFB2 Expression

BACKGROUND: 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. METHODS: 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 Ldha 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 β2) 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). RESULTS: 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 Tgfb2 knockdown reversed the prohypertrophic effects of histone lactylation in vivo, while Tgfb2 overexpression promoted cardiomyocyte hypertrophy via PI3K/AKT/mTOR (mechanistic target of rapamycin) signaling. Pharmacological inhibition of PI3K or AKT attenuated this effect. CONCLUSIONS: 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.