Acly, also known as adenosine 5'-triphosphate citrate lyase, is a cytosolic enzyme that converts citrate into acetyl-coenzyme A. This reaction is crucial for fatty acid and cholesterol biosynthesis, linking carbohydrate to lipid metabolism [1,2]. It is also involved in protein acetylation, and its expression changes are related to hyperlipidemia, cardiovascular diseases, and cancer [8]. Genetic models, such as gene knockout (KO) or conditional knockout (CKO) mouse models, have been valuable in studying its functions.

In cancer research, ACLY inhibition in immunocompetent mice was found to up-regulate PD-L1 expression in cancer cells, inducing T-cell dysfunction and immunosuppression. However, it also overcame cancer resistance to anti-PD-L1 therapy in a cGAS-dependent manner, likely due to polyunsaturated fatty acid peroxidation and mitochondrial DNA leakage that activates the cGAS-STING pathway [1]. In lipid metabolism and atherosclerosis studies, ACLY deficiency in hepatocytes protected from hepatic steatosis and dyslipidemia. Pharmacological inhibition of ACLY by bempedoic acid prevented dyslipidemia and attenuated atherosclerosis in hypercholesterolemic mice and miniature pigs [2]. In colon cancer, ACLY-deficient cell lines showed attenuated migration and invasion abilities, and ACLY promoted metastasis by stabilizing CTNNB1 protein [3]. In non-alcoholic fatty liver disease (NAFLD), Hrd1 interacted with and ubiquitinated Acly, reducing its protein level and suppressing lipogenesis, with Hrd1 overexpression ameliorating hepatic steatosis in db/db mice [4]. In hepatic ischemia-reperfusion injury, hepatic deficiency of Acly exacerbated injury, while restoration of Acly nuclear localization in the steatotic liver ameliorated the injury [5]. In oocyte maturation, autophagy in granulosa cells selectively degraded ACLY to maintain citrate homeostasis and promote oocyte maturation [6]. In CD8 T-cell function, ablation of ACLY triggered an alternative acetate-dependent pathway for acetyl-CoA production, and ACLY and ACSS2 coordinated cytosolic acetyl-CoA production to maintain chromatin accessibility and T-cell effector function [7]. In experimental colitis, ACLY-deficient CD4+ T cells showed an impaired capacity to induce intestinal inflammation, and butyrate suppressed ACLY expression in T cells, with tributyrin ameliorating chronic colitis [9].

In conclusion, Acly plays essential roles in multiple biological processes, including lipid metabolism, cancer development, oocyte maturation, and immune cell function. Gene knockout or conditional knockout mouse models have been instrumental in revealing its functions in diseases such as cancer, atherosclerosis, NAFLD, hepatic ischemia-reperfusion injury, and experimental colitis, providing potential therapeutic targets for these conditions.