Fig. 2

Metabolic determinants for Treg proliferation. During proliferation, Tregs exhibit decreased glycolysis but increased FAO. 1 The glycolytic rate is regulated by the PI3K-AKT-mTOR axis along with its upstream and downstream molecules, including AMPK and HIF-1α. AMPK inhibits glycolysis by downregulating mTOR activity. HIF-1α is activated by mTOR and modulates Treg proliferation through different mechanisms, including binding to Foxp3 and causing its degradation, as well as promoting the curbing of PDHK1 on PDH, resulting in a glycolysis shift and OXPHOS blockade. 2 AMPK activates CPT1 and drives mitochondrial FAO. LKB1, the upstream regulator of AMPK, engages the mevalonate pathway to produce cholesterol. SC-FA promotes Foxp3 expression by mediating histone H3 Ace in the promoter region of Foxp3. 3 BCAAs, IDO, tryptophan metabolites (3-HAA, kynurenine), glutamate, and arginine support Treg proliferation. AMPK AMP-activated protein kinase, HIF-1α hypoxia-inducible factor 1 α, PDHK1 pyruvate dehydrogenase kinase 1, L/S C-FA long/short-chain fatty acid, CPT1 carnitine palmitoyltransferase-1, LKB1 liver kinase B1, Ace acetylation, BCAA branched-chain amino acids, IDO indoleamine 2,3-dioxygenase, 3-HAA 3-hydroxyanthranillic acid (The process of mitochondria respiration was adapted from Fig. 1 in [139])