Abstract Body (Do not enter title and authors here): Backgroud:Metabolic and ventricular remodeling are early events of pressure overload that lead to heart failure. Metabolic remodeling is characterized by an imbalance between the tricarboxylic acid cycle and glycolysis.This imbalance increases glucose uptake by the heart, promotes glycolysis, and leads to its dissociation from oxidative phosphorylation, resulting in increased lactate production.Research Aim:To investigate whether there are genes that regulate the switching of energy metabolism patterns during pressure overload and act through lactate.Results:We used untargeted metabolomics to detect changes in metabolite content in transverse aortic constriction (TAC) mice and analyzed bulk RNA sequencing and single-cell sequencing data from public databases. Combined with a systematic literature review, we found that isocitrate dehydrogenase 2 (IDH2) plays an important role in switching energy metabolism modes, suggesting that IDH2 may be a potential therapeutic target.Silencing IDH2 in TAC mice using AAV resulted in an aggravated cardiac hypertrophy phenotype, accompanied by more extensive cardiac fibrosis compared to wild-type (WT) mice. On the contrary, overexpression of IDH2 by AAV attenuated cardiac hypertrophy in TAC mice. Mechanistically, IDH2 deficiency aggravates cardiomyocyte acidification, prompting cardiomyocytes to release lactate to maintain intracellular acid-base balance. Lactate, acting as a "signal molecule," is taken up by macrophages to promote H3K18 lactylation, which further enhances the expression of pro-inflammatory cytokines. In contrast, cardiac overexpression of IDH2 via AAV and administration of a lactate inhibitor alleviated cardiac hypertrophy and fibrosis.These findings suggest that lactate plays an important role in heart failure. Cardiomyocyte IDH2 can regulate the metabolic mode of cardiomyocytes and affect the lactate microenvironment, thereby altering the inflammatory state of macrophages and impacting pathological cardiac hypertrophy.Conclusion:IDH2 may be involved in the regulation of cardiac metabolism during pressure overload, leading to myocardial acidification, promoting the release of lactate and affecting the inflammatory state. This suggests the possibility of IDH2 as a potential therapeutic target and the nonmetabolic function of lactate as an intercellular signaling molecule. These findings will help to further explore the role of energy metabolic turnover in the occurrence and development of heart failure.