Citrate is the first product of the tricarboxylic acid cycle (TCA cycle), and this mitochondrially produced citrate is moved into the cytosol by the transporter SLC25A1. Citrate in the circulation is transported into cells by SLC13A5. A third source of citrate is that produced intracellularly by isocitrate dehydrogenase 1 (IDH1) from α-ketoglutarate (arising from glutamine metabolism) under conditions of hypoxic stress for example. ATP-citrate lyase (ACLY) converts cytosolic citrate into acetyl-CoA which is then utilised for lipogenesis. Targeting citrate transport and/or synthesis are mechanisms being explored for lipid-lowering potential and application to the treatment of chronic metabolic diseases that are characterised by dysregulated lipogenesis. Inhibition of IDH activity has been directed towards anti-tumour drug development, with two IDH inhibitors already in clinical use.

1. Lemieux RM, Popovici-Muller J, Travins J, Cai Z, Cui D, Zhou D. (2013) Therapeutically active compounds and their methods of use. Patent number: WO2013107291. Assignee: Agios Pharmaceuticals, Inc.. Priority date: 19/01/2012. Publication date: 25/07/2013.

2. Li JJ, Wang H, Tino JA, Robl JA, Herpin TF, Lawrence RM, Biller S, Jamil H, Ponticiello R, Chen L et al.. (2007) 2-hydroxy-N-arylbenzenesulfonamides as ATP-citrate lyase inhibitors. Bioorg Med Chem Lett, 17 (11): 3208-11. [PMID:17383874]

3. Wei J, Leit S, Kuai J, Therrien E, Rafi S, Harwood Jr HJ, DeLaBarre B, Tong L. (2019) An allosteric mechanism for potent inhibition of human ATP-citrate lyase. Nature, 568 (7753): 566-570. [PMID:30944472]

4. Zhang L, Hu W, Qiu Z, Li Z, Bian J. (2023) Opportunities and Challenges for Inhibitors Targeting Citrate Transport and Metabolism in Drug Discovery. J Med Chem, 66 (14): 9229-9250. [PMID:37428122]