Molecular Targets and Small Molecules Modulating Acetyl Coenzyme A in Physiology and Diseases

Acetyl coenzyme A (acetyl-CoA), a pivotal regulatory metabolite, is a product of numerous catabolic reactions and a substrate for various anabolic responses. Its role extends to crucial physiological processes, such as glucose homeostasis and free fatty acid utilization. Moreover, acetyl-CoA plays a significant part in reshaping the metabolic microenvironment and influencing the progression of several diseases and conditions, including cancer, insulin resistance, diabetes, heart failure, fear, and neuropathic pain. This Review delves into the role of acetyl-CoA in both physiological and pathological conditions, shedding light on the key players in its formation within the cytosol. We specifically focus on the physiological impact of malonyl-CoA decarboxylase (MCD), acetyl-CoA synthetase2 (ACSS2), and ATP-citrate lyase (ACLY) on metabolism, glucose homeostasis, free fatty acid utilization, and post-translational modification cellular processes. Additionally, we present the pathological implications of MCD, ACSS2, and ACLY in various clinical manifestations. This Review also explores the potential and limitations of targeting MCD, ACSS2, and ACLY using small molecules in different clinical settings.