ACC1 inhibition enhances BCG-induced trained immunity by reprogramming Acetyl-CoA metabolism

Trained immunity enhances long-term innate immune responsiveness through metabolic and epigenetic rewiring. Using BCG as a model, we demonstrate that inhibition of acetyl-CoA carboxylase 1 (ACC1) enhances BCG-induced trained immunity by increasing intracellular acetyl-CoA (ACoA) availability. This shift redirects ACoA from lipid biosynthesis towards enhanced tricarboxylic acid (TCA) cycle flux and histone acetylation, reinforcing metabolic and epigenetic programs that sustain trained immunity. ACC1 inhibitors amplify cytokine production, mitochondrial respiration, and glutamine metabolism in monocytes, with heightened histone H3K27 acetylation and reduced H3K9 methylation at pro-inflammatory loci. In vivo, ACC1 inhibition amplified BCG-driven myelopoiesis, increasing granulocyte-macrophage progenitors and systemic cytokine responses. Notably, genetic variation in ACoA metabolism genes influenced trained immunity responses in BCG-vaccinated individuals. These findings highlight ACC1 as a metabolic checkpoint linking cellular metabolism to innate immune memory. Targeting ACoA metabolism may represent a promising strategy to optimize vaccine efficacy and enhance broad-spectrum protection against infections.