Glycolysis involves the conversion of glucose molecules into various metabolic by-products, culminating in the end product pyruvate as well as two net ATPs. In macrophages treated with IL-4 (M[IL-4], left side of the cell) pyruvate (and fatty acids) enters the intact TCA cycle as acetyl-CoA, thus resulting in sustained ATP production via OXPHOS and leading to the upregulation of genes associated with tissue repair. In contrast, in macrophages treated with LPS and IFNγ (M[LPS+IFNγ], right side of the cell), most pyruvate is converted into lactate and secreted. Furthermore, the enzyme CARKL is downregulated, and as a result, glycolysis also feeds the PPP, thereby generating nucleotides, amino acids, and NADPH. The TCA cycle is broken in two places in M[LPS+IFNγ] macrophages, thus resulting in the accumulation of citrate, which in turn is used to drive fatty acid synthesis (FAS) and succinate, which stabilizes the transcription factor HIF-1α. HIF-1α enters the nucleus and promotes the expression of hypoxia response element (HRE)-containing genes, which encode both glycolytic and proinflammatory proteins such as IL-1β). The disturbed TCA cycle and decreased OXPHOS also result in increased levels of ROS, which further stabilize HIF-1α, allowing it to drive glycolysis and inflammatory-gene expression. G6P, glucose 6-phosphate; F6P, fructose 6-phosphate; OAA, oxaloacetate.