ACLY (ATP citrate lyase) catalyzes the cleavage of citrate into oxaloacetate and acetyl-CoA, serving as a critical hub linking nutrient metabolism to biosynthetic and epigenetic processes 1. The enzyme operates at the intersection of mitochondrial metabolism and cytosolic lipogenesis, controlling fatty acid and cholesterol synthesis while generating acetyl-CoA for histone acetylation 23. Beyond canonical metabolic functions, ACLY-derived acetyl-CoA acts as a signaling metabolite regulating mitophagy through direct binding to NLRX1 4 and modulates ferroptosis susceptibility via FSP1 acetylation 5. ACLY dysregulation contributes to multiple diseases. In hepatocellular carcinoma (HCC), ACLY inhibition reduces tumor burden over 70% by reprogramming tumor immunity, increasing chemokine CXCL13, tumor-infiltrating B cells, and tertiary lymphoid structures 1. In neuroinflammation, ACLY-p300 interactions control epigenetic memory in disease-associated astrocytes, promoting CNS pathology in experimental autoimmune encephalomyelitis and multiple sclerosis 6. ACLY also regulates exhausted CD8+ T cell differentiation through citrate-dependent histone acetylation at TEX signature genes 7. Clinically, ACLY represents a promising therapeutic target. The selective inhibitor EVT0185 demonstrates efficacy in MASH-HCC as monotherapy and synergizes with tyrosine kinase inhibitors and immunotherapies 1. ACLY inhibition combined with immune checkpoint inhibitors or ferroptosis inducers offers potential multi-modal treatment strategies across cancer types.