ACSS2, also known as acetyl-CoA synthetase 2 or acyl-CoA synthetase short-chain family member 2, is an enzyme that converts acetate to acetyl-CoA. Acetyl-CoA is crucial for multiple cellular processes such as fatty acid synthesis, ATP production, and protein acetylation [3]. It is also involved in pathways related to histone modification, which impacts gene expression, and is important for cell survival, metabolism, and tissue plasticity [1,2,4,5]. Genetic models, like KO mouse models, have been valuable in studying its functions.

In KO mouse models, ACSS2-KO mice are protected from kidney fibrosis in multiple disease models, as ACSS2 in primary tubular cells regulates de novo lipogenesis, leading to NADPH depletion, increased ROS levels, and NLRP3-dependent pyroptosis [7]. In cancer research, genetic depletion of ACSS2 in tumors inhibits the growth of various cancers, such as triple-negative breast cancer and pancreatic cancer [3,6]. In the context of Alzheimer's disease, reducing ACSS2 levels in 5×FAD mice leads to cognitive impairment, while upregulating ACSS2 or replenishing its substrate (acetate) rescues synaptic plasticity and cognitive function [2].

In conclusion, ACSS2 is essential for maintaining normal cellular metabolism, histone modification-related gene expression, and tissue function. KO mouse models have been instrumental in revealing its role in diseases like kidney fibrosis, cancer, and Alzheimer's disease. Understanding ACSS2 through these models provides potential therapeutic targets for these disease areas.

References:

1. Zhu, Rongxuan, Ye, Xianglai, Lu, Xiaotong, Tao, Yizhi Jane, Lu, Zhimin. 2024. ACSS2 acts as a lactyl-CoA synthetase and couples KAT2A to function as a lactyltransferase for histone lactylation and tumor immune evasion. In Cell metabolism, 37, 361-376.e7. doi:10.1016/j.cmet.2024.10.015. https://pubmed.ncbi.nlm.nih.gov/39561764/

2. Lin, Yingbin, Lin, Anlan, Cai, Lili, Chen, Xiaochun, Zhang, Jing. 2023. ACSS2-dependent histone acetylation improves cognition in mouse model of Alzheimer's disease. In Molecular neurodegeneration, 18, 47. doi:10.1186/s13024-023-00625-4. https://pubmed.ncbi.nlm.nih.gov/37438762/

3. Miller, Katelyn D, Pniewski, Katherine, Perry, Caroline E, Salvino, Joseph M, Schug, Zachary T. 2021. Targeting ACSS2 with a Transition-State Mimetic Inhibits Triple-Negative Breast Cancer Growth. In Cancer research, 81, 1252-1264. doi:10.1158/0008-5472.CAN-20-1847. https://pubmed.ncbi.nlm.nih.gov/33414169/

4. Chen, Nuo, Zhao, Ming, Wu, Nan, Li, Yan, Zhang, Lining. 2024. ACSS2 controls PPARγ activity homeostasis to potentiate adipose-tissue plasticity. In Cell death and differentiation, 31, 479-496. doi:10.1038/s41418-024-01262-0. https://pubmed.ncbi.nlm.nih.gov/38332049/

5. Li, Xinjian, Yu, Willie, Qian, Xu, Jiang, Tao, Lu, Zhimin. 2017. Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy. In Molecular cell, 66, 684-697.e9. doi:10.1016/j.molcel.2017.04.026. https://pubmed.ncbi.nlm.nih.gov/28552616/

6. Murthy, Divya, Attri, Kuldeep S, Shukla, Surendra K, Wellen, Kathryn E, Singh, Pankaj K. 2024. Cancer-associated fibroblast-derived acetate promotes pancreatic cancer development by altering polyamine metabolism via the ACSS2-SP1-SAT1 axis. In Nature cell biology, 26, 613-627. doi:10.1038/s41556-024-01372-4. https://pubmed.ncbi.nlm.nih.gov/38429478/

7. Mukhi, Dhanunjay, Li, Lingzhi, Liu, Hongbo, Wellen, Kathryn E, Susztak, Katalin. 2023. ACSS2 gene variants determine kidney disease risk by controlling de novo lipogenesis in kidney tubules. In The Journal of clinical investigation, 134, . doi:10.1172/JCI172963. https://pubmed.ncbi.nlm.nih.gov/38051585/