Acss2, short for acetyl-CoA synthetase 2, is an enzyme that plays crucial roles in multiple biological processes. It is involved in the conversion of acetate to acetyl-CoA, which is essential for fatty acid synthesis, ATP production, and protein acetylation. It also participates in histone modification-related pathways, such as histone acetylation, lactylation, and crotonylation, influencing gene expression and various biological functions [1-5].

In multiple disease models, Acss2 has shown significant impacts. In Alzheimer's disease mouse models, reduced Acss2 expression was associated with decreased histone acetylation, impaired synaptic plasticity, and cognitive decline, while upregulating Acss2 or providing its substrate acetate rescued these deficits [1]. In triple-negative breast cancer, genetic depletion of Acss2 and pharmacological inhibition using a transition-state mimetic inhibitor impaired tumor growth [2]. In kidney fibrosis models, inhibition of Acss2-mediated histone crotonylation alleviated fibrosis by suppressing IL-1β-dependent macrophage activation and tubular cell senescence [3]. In pancreatic cancer, blocking the Acss2-SP1-SAT1 axis diminished tumor burden in mouse models [4]. In pancreatic neuroendocrine neoplasms, hypoxia-upregulated Acss2 promoted tumor progression through lipid metabolism reprogramming, and knockdown or inhibition of Acss2 inhibited this process [5].

In conclusion, Acss2 is a key regulator in multiple biological processes, especially those related to metabolism and gene expression through histone modification. Gene knockout or conditional knockout mouse models have been instrumental in revealing its role in diseases such as Alzheimer's disease, various cancers, and kidney fibrosis. Understanding Acss2's functions provides potential therapeutic targets for these diseases.