Citrate synthase (CS) is a key mitochondrial enzyme catalyzing the first committed step of the tricarboxylic acid (TCA) cycle, condensing acetyl-CoA and oxaloacetate to form citrate. Located in the mitochondrial matrix, CS plays a central role in aerobic energy metabolism and carbohydrate metabolism [GO annotations]. The enzyme's function is critical for cellular respiration and ATP production, particularly under conditions requiring oxidative phosphorylation. CS expression and activity can be modulated to shift cellular metabolism from glycolysis toward mitochondrial respiration 1, which has therapeutic implications for cancer treatment strategies including cuproptosis sensitization. In this context, increasing CS-mediated TCA cycle flux depletes endogenous antioxidants and sensitizes tumor cells to copper-induced cell death 1. Beyond its canonical metabolic role, CS localizes to both mitochondria and the nucleus [GO annotations], suggesting potential regulatory functions beyond energetics. CS also exhibits RNA-binding capacity [GO annotations], indicating broader cellular roles. Clinical significance includes metabolic reprogramming in cancer therapy, where enhancing mitochondrial respiration through CS-dependent pathways represents an emerging strategy to overcome resistance mechanisms in malignancies.