Figure 9. Mechanism of metabolic reprogramming.

Graphical summary of the metabolic basis of GEM resistance in UC cells. GR cells demonstrate 2‐HG production by reductive glutamine metabolism stimulated by IDH2 gain of function. The increase of 2‐HG production suppresses PHD2 function and stabilizes Hif‐1α expression, which regulates the key metabolic enzymes TIGAR, TKT, and CTPS1, which are involved with aerobic glycolysis and PPP bypass. With the stimulation of aerobic glycolysis metabolism, it promotes the generation of dCTP for acquiring therapeutic competition against GEM. At the same time, oxidative PPP stimulation increases NADPH/NADP production and enhances antioxidant defense, which facilitates cross‐resistance to CDDP. Thus, inhibition of IDH2 suppress the entire metabolic reprogramming and therefore restore both GEM and CDDP sensitivity in UC cells.