Fig. 3

Mechanisms of microglial metabolic reprogramming during stroke progression. In the early stage of stroke, the hypoxic environment stabilizes hypoxia-inducible factor-1α protein by inhibiting prolyl hydroxylase activity. HIF-1α subsequently drives the expression of glycolytic genes, prompting cells to preferentially generate ATP rapidly via glycolysis. As stroke progresses and energy stress occurs, the increased intracellular AMP/ATP ratio activates the energy sensor AMP-activated protein kinase. Activated AMPK inhibits the activity of the mTORC1 complex by phosphorylating its key component Raptor, leading to decreased expression of key glycolytic enzymes, gradual shutdown of glycolytic metabolism, and concurrent initiation of fatty acid oxidation. AMPK promotes fatty acid oxidation through two parallel pathways: on one hand, AMPK phosphorylates and inhibits acetyl-CoA carboxylase, reducing the production of malonyl coenzyme A, thereby relieving the inhibition of carnitine palmitoyl transferase 1 A and accelerating the entry of long-chain fatty acids into mitochondria for β-oxidation; on the other hand, AMPK can enhance the transcriptional activity of PPARα. PPARα upregulates the expression of fatty acid oxidation-related enzymes and mitochondrial biogenesis genes by recognizing and binding to the peroxisome proliferator response element in the promoter regions of target genes. (HIF-1α, Hypoxia-inducible factor-1α; PHD, Prolyl hydroxylase; AMPK, AMP-activated protein kinase; mTORC1, mammalian target of rapamycin complex 1; ACC, Acetyl-CoA carboxylase; malonyl-CoA, malonyl coenzyme A; CPT1A, Carnitine Palmitoyl Transferase 1 A; LCFAs, Long-chain fatty acids; PPARα, Peroxisome Proliferator-Activated Receptor α; PPRE, Peroxisome Proliferator Response Element.). This Figure is original. Created with MedPeer (medpeer.cn)