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Acyl\u2010CoA synthetase short\u2010chain family member 2 (ACSS2) is a key enzyme that converts acetate into acetyl\u2010CoA, fueling de novo lipogenesis and histone acetylation. In obesity, ACSS2 expression is transcriptionally induced by sterol regulatory element\u2010binding proteins (SREBPs) and carbohydrate response element\u2010binding 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\u2010related disorders through its dual regulation of lipid synthesis and epigenetic modification. In most obesity\u2010associated 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\u2010dependent 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\u2010evoked metabolic disorders and cancer progression linked by ACSS2 and suggests future studies on understanding ACSS2 regulatory mechanisms, therapeutic potential, and biomarker utility across obesity\u2010associated diseases.<\/jats:p>","DOI":"10.1111\/obr.70096","type":"journal-article","created":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T05:55:05Z","timestamp":1768542905000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Fueling Disease: ACSS2 in Obesity\u2010Associated Metabolic Disorders and Cancer Progression"],"prefix":"10.1111","volume":"27","author":[{"given":"Liuting","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Pathogenic Biology, School of Medicine Nantong University  Jiangsu 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