Targeting ATP-Citrate Lyase Across Cardiometabolic and Oncologic Disease

ATP-citrate lyase (ACLY) is a key metabolic enzyme that links mitochondrial citrate export to the generation of cytosolic acetyl-CoA, thereby supporting de novo lipogenesis, cholesterol biosynthesis, protein acetylation, chromatin remodelling, and transcriptional control. Interest in ACLY inhibition initially arose from its lipid-lowering properties and led to the clinical development of bempedoic acid, whose ability to reduce low-density lipoprotein cholesterol and improve cardiovascular outcomes now provides the strongest clinical proof of concept for targeting this pathway. Beyond dyslipidaemia, preclinical evidence suggests that targeting the ACLY pathway and related bempedoic acid-responsive metabolic programs may ameliorate metabolic dysfunction-associated steatotic liver disease (MASLD). ACLY inhibition is expected to reduce de novo fatty-acid and cholesterol synthesis by limiting cytosolic acetyl-CoA availability, whereas parent bempedoic acid can directly activate PPARα, and thereby enhance fatty-acid oxidation. However, unlike the cardiovascular setting, robust clinical data supporting ACLY inhibition in MASLD are still lacking. More recently, the identification of nuclear ACLY functions has substantially expanded its biological significance, establishing ACLY as a metabolic-epigenetic integrator that couples nutrient availability to chromatin remodelling, transcriptional programs and immune responses. In cancer, dysregulated ACLY activity contributes to tumour growth, metabolic plasticity, therapy resistance and immune evasion, and its inhibition has shown promising antitumour effects in preclinical models. This review summarizes ACLY biology and pharmacology, emphasizing established cardiovascular applications, emerging MASLD opportunities and exploratory oncologic indications, while highlighting unresolved translational questions.