Metabolic reprogramming of myeloid cells during activation and inflammation resolution. (A) Upon activation (e.g., by pathogens or DAMPs), microglia increase glucose uptake, which is metabolized through glycolysis and the pentose phosphate pathway (PPP). Glycolysis generates pyruvate and acetyl-CoA, while the PPP produces NADPH necessary for fatty acid synthesis and ROS generation. Inflammatory stimuli block the TCA cycle, diverting citrate to the cytosol, where ATP-citrate lyase (ACLY) converts it into acetyl-CoA. This cytosolic acetyl-CoA supports histone acetylation in the nucleus, opening chromatin and facilitating NF-κB binding, thereby promoting transcription of pro-inflammatory genes. (B) In the resolution state, lipid uptake (e.g., from extracellular debris) leads to intracellular fatty acid generation. These fatty acids undergo β-oxidation in mitochondria, producing acetyl-CoA that feeds into the TCA cycle, fueling OXPHOS and ATP production. Fatty acids also serve as ligands for PPARs, which inhibit NF-κB–mediated transcription, thus promoting anti-inflammatory signaling and immunometabolic homeostasis. Me, Methylation; Ac, Acetylation; a-KG, a-ketoglutarate; iNOS, nitric oxide synthase.