Adenosine Triphosphate-Citrate Lyase (ATP-citrate lyase) is a crucial enzyme in the production of fatty acids. Because these disorders frequently involve dysregulated lipid metabolism, inhibiting this enzyme has sparked great attention as a potential therapeutic approach for conditions such as obesity, metabolic syndrome, and certain malignancies. Several ATP-citrate lyase inhibitors have been investigated, albeit not all have reached clinical trials. Polyphenols, such as (-)-hydroxycitric acid (HCA) produced from Garcinia cambogia, are one notable type of ATP-citrate lyase inhibitors. HCA gained popularity due to its reported ability to block ATP-citrate lyase, potentially lowering the conversion of citrate to acetyl-CoA, a precursor in the creation of fatty acids. However, while animal and cell culture experiments have yielded encouraging findings, human trials have been equivocal, underscoring the need for further research. Small molecules or synthesized substances are used in another class of ATP-citrate lyase inhibitors. Certain pharmacological drugs, such as ND-630 and bempedoic acid, have been shown to inhibit ATP-citrate lyase. In some areas, bempedoic acid has been approved as a supplement to diet and maximally tolerated statin medication for people with heterozygous familial hypercholesterolemia or existing atherosclerotic cardiovascular disease. Furthermore, natural substances such as soraphen A, isolated from Sorangium cellulosum, block ATP-citrate lyase potently. In preclinical investigations, Soraphen A reduced lipid synthesis and suppressed tumor growth in certain malignancies, yielding promising results. However, issues with absorption and potential adverse effects have stymied its development to clinical application. The development of ATP-citrate lyase inhibitors in humans presents challenges in terms of selectivity, efficacy, and safety. While some drugs have shown efficacy in preclinical models, their translation to clinical settings is frequently fraught with complications, such as off-target effects or low bioavailability. Continued study into ATP-citrate lyase inhibitors could help treat metabolic problems and certain malignancies. Improved understanding of the enzyme's role in cellular metabolism, as well as advances in drug design techniques, may pave the way for the development of more effective and safer ATP-citrate lyase inhibitors, potentially opening up new therapeutic avenues for a variety of diseases associated with altered lipid metabolism.
