Acly, also known as adenosine 5'-triphosphate citrate lyase, is a cytosolic enzyme that plays a crucial role in cellular metabolism. It converts citrate into acetyl-coenzyme A, which is an essential precursor for fatty acid and cholesterol biosynthesis [1,2]. This enzyme links carbohydrate to lipid metabolism, and its activity impacts various biological processes such as cell growth, division, and immunomodulation. Genetic models, like KO/CKO mouse models, have been instrumental in studying Acly's functions.

In cancer research, inhibition of Acly in immunocompetent mice was found to up-regulate PD-L1 expression in cancer cells, leading to T cell dysfunction and immunosuppression. However, it also overcame cancer resistance to anti-PD-L1 therapy in a cGAS-dependent manner, likely through polyunsaturated fatty acid peroxidation and mitochondrial damage that activate the cGAS-STING pathway [1].

In hepatocytes, Acly deficiency protected from hepatic steatosis and dyslipidemia, and pharmacological inhibition of Acly by bempedoic acid prevented dyslipidemia and attenuated atherosclerosis in hypercholesterolemic mouse models [2].

In colon cancer cell lines, ACLY-deficient cells showed attenuated migration and invasion abilities, and in a mouse model, ACLY was shown to promote metastasis by stabilizing CTNNB1 protein [3].

In the context of non-alcoholic fatty liver disease (NAFLD), Hrd1, a subunit of the endoplasmic reticulum-associated degradation complex, interacted with and ubiquitinated Acly in db/db mice, reducing its protein level and suppressing lipogenesis [4].

In liver ischemia-reperfusion injury, hepatocyte-specific knockout of Acly exacerbated injury, while restoring Acly nuclear localization in steatotic livers ameliorated the injury [5].

In mucosal T cells, ACLY-deficient CD4+ T cells had an impaired capacity to induce intestinal inflammation in a transfer colitis model, and modulation of ACLY expression in T cells could be a strategy to resolve intestinal inflammation [6].

In conclusion, Acly is essential for lipid metabolism, playing a significant role in various disease conditions such as cancer, atherosclerosis, NAFLD, and colitis. Gene knockout and conditional knockout mouse models have been crucial in revealing these functions, providing insights into potential therapeutic targets for these diseases.