The origin of metabolic syndrome, a pathophysiological condition facilitating cardiovascular disease, diabetes, and other comorbidities, remains poorly understood. Recent work by Xiao et al (2023) identifies the mitochondrial enzyme ACSM3 as a determinant of lipid homeostasis and hepatic health in mice and patients. Additionally, the authors identified deleterious downstream p38-MAPK signalling as a targetable feature of ACSM3 deficiency that may help to ameliorate metabolic syndrome.