9r90 | pdb_00009r90
Cryo-EM structure of human ATP citrate lyase in complex with inhibitor EVT0185-CoA
Structural highlights
FunctionACLY_HUMAN ATP citrate-lyase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. Has a central role in de novo lipid synthesis. In nervous tissue it may be involved in the biosynthesis of acetylcholine.[1] Publication Abstract from PubMedImmunosuppressive tumour microenvironments are common in cancers such as metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma (HCC) (MASH-HCC)(1-3). Although immune cell metabolism influences effector function, the effect of tumour metabolism on immunogenicity is less understood(4). ATP citrate lyase (ACLY) links substrate availability and mitochondrial metabolism with lipid biosynthesis and gene regulation(5-7). Although ACLY inhibition shows antiproliferative effects in various tumours, clinical translation has been limited by challenges in inhibitor development and compensatory metabolic pathways(8-12). Here, using a mouse model of MASH-HCC that mirrors human disease, genetic inhibition of ACLY in hepatocytes and tumours reduced neoplastic lesions by over 70%. To evaluate the therapeutic potential of this pathway, a novel small-molecule ACLY inhibitor, EVT0185 (6-[4-(5-carboxy-5-methyl-hexyl)-phenyl]-2,2-dimethylhexanoic acid), was identified via phenotypic screening. EVT0185 is converted to a CoA thioester in the liver by SLC27A2 and structural analysis by cryo-electron microscopy reveals that EVT0185-CoA directly interacts with the CoA-binding site of ACLY. Oral delivery of EVT0185 in three mouse models of MASH-HCC dramatically reduces tumour burden as monotherapy and enhances efficacy of current standards of care including tyrosine kinase inhibitors and immunotherapies. Transcriptomic and spatial profiling in mice and humans linked reduced tumour ACLY with increases in the chemokine CXCL13, tumour-infiltrating B cells and tertiary lymphoid structures. The depletion of B cells blocked the antitumour effects of ACLY inhibition. Together, these findings illustrate how targeting tumour metabolism can rewire immune function and suppress cancer progression in MASH-HCC. ACLY inhibition promotes tumour immunity and suppresses liver cancer.,Gautam J, Wu J, Lally JSV, McNicol JD, Fayyazi R, Ahmadi E, Oniciu DC, Heaton S, Newton RS, Rehal S, Bhattacharya D, Di Pastena F, Nguyen B, Valvano CM, Townsend LK, Banskota S, Batchuluun B, Jabile MJT, Payne A, Lu J, Desjardins EM, Kubota N, Tsakiridis EE, Mistry B, Aganostopoulos A, Houde V, Dansercoer A, Verschueren KHG, Savvides SN, Hammill JA, Bezverbnaya K, Muti P, Tsakiridis T, Dai W, Jiang L, Hoshida Y, Larche M, Bramson JL, Friedman SL, Verstraete K, Wang D, Steinberg GR Nature. 2025 Sep;645(8080):507-517. doi: 10.1038/s41586-025-09297-0. Epub 2025 , Jul 30. PMID:40739358[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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