Acetyl-CoA synthetase 2 (ACSS2) is an enzyme that has diverse and crucial functions. It converts acetate to acetyl-CoA, which is a vital metabolite for many cellular processes such as fatty acid synthesis, ATP production, and protein acetylation. It is also involved in histone modifications like acetylation, lactylation, and crotonylation, thereby regulating gene expression and participating in multiple biological pathways [1-10].

Genetic depletion of ACSS2 in tumors has shown to inhibit the growth of various cancers, suggesting its potential as a therapeutic target for breast cancer [2]. In 5×FAD mice (a model for Alzheimer's disease), reducing ACSS2 levels led to decreased histone acetylation and cognitive impairment, while upregulating ACSS2 or supplementing acetate rescued synaptic plasticity and cognitive function [1]. In ACSS2-KO mice, protection from kidney fibrosis was demonstrated, as ACSS2 was found to regulate de novo lipogenesis in kidney tubules, affecting ROS levels and NLRP3-dependent pyroptosis [3].

In conclusion, ACSS2 is a key enzyme in multiple biological processes, with its functions in histone modification and metabolism significantly influencing gene expression. The use of gene-knockout mouse models, like those for cancer, Alzheimer's disease, and kidney disease, has revealed ACSS2's role in disease development, providing potential therapeutic strategies for these conditions.