Fig. 1

The Dual Role of ACSS2 and its Correlation to Metabolic Diseases: ACSS2, with its nucleo-cytosolic nature, plays a significant role in the development of metabolic diseases by participating in various lipogenic or regulatory pathways: (1) ACSS2 Cytosolic Lipogenic Role: Upon the consumption of a high-fat diet, excess fats are metabolized by colonic microbiota into acetate. ACSS2, in its deacetylated active form, converts this exogenous acetate or that from endogenous histone deacetylation reactions into acetyl-CoA. This acetyl-CoA normally functions in the fatty acid oxidation in the mitochondria or in lipid synthesis by feeding the de novo lipogenesis pathway (DNL). Overexpression of ACSS2, associated with the manifestations of metabolic diseases, promotes increased lipid synthesis via DNL and fat deposition. This leads to the development of insulin resistance, disrupting cellular homeostasis and triggering the release of proinflammatory cytokines—features linked to obesity, diabetes, and MAFLD. Additionally, lipid accumulation elevates reactive oxygen species (ROS) and NLRP3-inflammasome-mediated kidney fibrosis. Enhanced fatty acid oxidation (FAO) also supports T-cell differentiation, contributing to heightened immune responses. (2) ACSS2 Nuclear Regulatory Role: Under stress conditions, such as hypoxia, nutrient deprivation, or cellular damage, ACSS2 phosphorylation exposes its nuclear localization signal, facilitating its translocation into the nucleus. In the nucleus, ACSS2 plays regulatory roles by promoting histone acetylation and activating the transcription of genes that support cell survival under stress conditions. ACSS2 activates genes involved in lipid synthesis and metabolism, further enhancing DNL and increasing fat accumulation, which is associated with NAFLD. It also activates genes that promote tumorigenesis, epithelial-to-mesenchymal transition (EMT), and proinflammatory cytokine production. Furthermore, ACSS2’s role in histone acetylation activates the mTOR pathway, inhibiting autophagy and disrupting normal cellular functions, leading to complications such as kidney injury in diabetic conditions, also known as diabetic nephropathy. ACSS2 overexpression also promotes kidney fibrosis through IL1b secretion and macrophage activation. This dual role of ACSS2, both in the cytosol and the nucleus, underscores its significance in metabolic diseases and highlights potential therapeutic targets for intervention. (Figure designed using BioRender with a publication license.)