Fueling Disease: ACSS2 in Obesity‐Associated Metabolic Disorders and Cancer Progression

Obesity is a major risk factor for metabolic disorders and cancer, largely due to dysregulated nutrient sensing and metabolic reprogramming. Acyl-CoA synthetase short-chain family member 2 (ACSS2) is a key enzyme that converts acetate into acetyl-CoA, fueling de novo lipogenesis and histone acetylation. In obesity, ACSS2 expression is transcriptionally induced by sterol regulatory element-binding proteins (SREBPs) and carbohydrate response element-binding protein (ChREBP), while phosphorylation and dephosphorylation at specific residues (e.g., S659, S263, and T363) further modulate its enzymatic activity and subcellular localization. Emerging evidence shows the pathogenic roles of ACSS2 in obesity-related disorders through its dual regulation of lipid synthesis and epigenetic modification. In most obesity-associated cancers, ACSS2 is upregulated in tumor cells to enhance acetate utilization and promote growth. By contrast, in digestive system tumors, ACSS2 downregulation enables metabolic plasticity by shifting from acetate metabolism toward aerobic glycolysis, thereby favoring malignant progression. Concurrently, ACSS2 downregulation in T cells under chronic antigen exposure compromises antitumor immunity, underscoring its context-dependent role in shaping tumor metabolism and immune evasion. Notably, its nuclear localization is frequently associated with greater malignancy and poorer prognosis. Stratified analyses further suggest its prognostic value may be enhanced in individuals with obesity. Although ACSS2 inhibitors have shown therapeutic promise in preclinical studies, only one has progressed to clinical trials, highlighting the need for continued translational research. This review summarizes current insights for obesity-evoked metabolic disorders and cancer progression linked by ACSS2 and suggests future studies on understanding ACSS2 regulatory mechanisms, therapeutic potential, and biomarker utility across obesity-associated diseases.