ATP Citrate Lyase in Metabolic Disease: Mechanistic Insights and Clinical Potential

Abstract

Metabolic reprogramming is a hallmark of many human diseases, including cancer, metabolic dysfunction, cardiovascular disease, and chronic inflammation. By reshaping bioenergetic and biosynthetic pathways, cells adapt to environmental stress and altered functional demands. Acetyl‐coenzyme A (acetyl‐CoA) plays a pivotal role in this process, as it supports both lipogenesis and protein acetylation, thereby linking cellular metabolism to epigenetic and transcriptional regulation. ATP citrate lyase (ACLY) is a rate‐limiting enzyme that converts citrate‐derived carbon flux from the tricarboxylic acid (TCA) cycle into acetyl‐CoA and thus occupying a central position in metabolic regulation. Growing evidence identifies ACLY as a metabolic regulator with broad pathological relevance across diverse diseases, including cardiovascular disease, cancer, and metabolic dysfunction‐associated steatotic liver disease (MASLD). Pharmacological inhibition of ACLY has been shown to lower low‐density lipoprotein cholesterol (LDL‐C) levels and reduce cardiovascular risk, whereas emerging studies further support its therapeutic potential in metabolic dysfunction‐associated steatohepatitis (MASH). This review summarizes the structure, catalytic mechanisms, and biological functions of ACLY, with particular emphasis on its roles in disease pathogenesis. It further discusses the development of ACLY inhibitors, ranging from early competitive inhibitors to liver‐directed prodrugs, and highlights their clinical translation as promising multifunctional therapies for metabolic and related diseases.