ACSF3 is a mitochondrial acyl-CoA synthetase that catalyzes the ATP-dependent activation of malonate and methylmalonate into their respective CoA thioesters, with some preference for very-long-chain substrates 123. The enzyme's primary metabolic role is to clear malonate—a potent inhibitor of succinate dehydrogenase in the TCA cycle—by converting it to malonyl-CoA, which is subsequently decarboxylated to acetyl-CoA 4. Additionally, ACSF3-derived malonyl-CoA serves as a substrate for protein lysine malonylation within the mitochondrial matrix, providing post-translational regulatory control of mitochondrial metabolism 45. Biallelic ACSF3 variants cause combined malonic and methylmalonic aciduria (CMAMMA), characterized by elevated urinary malonic and methylmalonic acid 6. While historically considered benign, recent evidence expands the clinical phenotype to include developmental delay, seizures, and Lennox-Gastaut Syndrome in severe cases, with comorbid autism and intellectual disability 7. A regulatory variant (rs34590044-A) upregulating ACSF3 expression was positively selected in anatomically modern humans over the past 20,000 years, correlating with increased height and basal metabolic rate adaptation to meat-enriched diets 8. Genetic analysis confirms ACSF3 mutations through newborn screening programs, facilitating early diagnosis and intervention 9.