Abstract Body (Do not enter title and authors here): Introduction: Mutations in DNA methyltransferase 3 alpha (DNMT3A) are the most common trigger of clonal hematopoiesis of indeterminant potential (CHIP) and are associated with higher risk of cardiovascular disease and proinflammatory activation of immune cells. Hypothesis: we hypothesize that driver mutations modulate the epigenetic status of metabolic signaling pathways, triggering the pro-inflammatory phenotype in immune cells. Objectives: We aim to define the epigenetic-metabolic status of patients with CHIP driver mutations and to describe the contribution of the affected metabolic pathways to the pro-inflammatory phenotypes in the patients and finally to apply metabolic modulation as a therapeutic approach. Methods: We checked DNA methylation and metabolic status of patients with heart failure (HF) and chronic obstructive pulmonary disease (COPD) with CHIP DNMT3A mutations and non-CHIP. The activity of mitochondrial complexes in patients' macrophages was measured by Seahorse analysis. We used mice with Dnmt3a mutations in hematopoietic stem cells (DNMT3A-mut mice; Dnmt3a^WT/R882H) to test the therapeutic efficiency of metabolic modulators in the myocardial infarction mouse model. Results: HF and COPD patients with DNMT3A mutations CHIP show a hypomethylated DNA profile and elevated tricarboxylic acid (TCA) metabolites, particularly malate. Macrophages from DNMT3A CHIP mutation carriers demonstrated DNA hypomethylation of succinate dehydrogenase A (SDHA) promoter, altered TCA cycle metabolite profiles, and augmented mitochondrial complex II activity. DNMT3A ablation in macrophages mimicked DNMT3A CHIP condition by raising SDHA mRNA and protein levels also enhancing mitochondrial complex II activity. DNMT3 CHIP macrophages enhanced pro-inflammatory phenotype in wild-type macrophages through secretion of malate in paracrine manner, sourced from complex II, under baseline and inflammatory conditions. Pharmacological inhibition of SDHA with dimethylmalonate in DNMT3A-mut mice improved the inflammatory response and cardiac function after myocardial infarction through reduction pro-inflammatory response. Conclusion: Intervention of altered metabolism may represent a new therapeutic option to mitigate inflammatory activation in patients with DNMT3A CHIP.