Fig. 2.

Molecular mechanisms of NADPH homeostasis in cancer. The principal generation of NADPH (blue) with dysregulated pathways and enzymes (red) in cancer: (i) NADKs catalyze the phosphorylation of NAD(H) to form NADP(H) via the de novo synthesis (cNADK in the cytosol and mNADK in mitochondria). (ii) the pentose phosphate pathway (PPP) utilizes G6PD and PGD to maintain the cytosolic NADPH. (iii) the folate-mediated one-carbon metabolism reduces NADP⁺ to NADPH by MTHFD1/ALDH1L1 in the cytosol, MTHFD2/MTHFD2L/ALDH1L2 in mitochondria and DHFR in the nucleus. (iv) IDH1 located in the cytosol and IDH2 located in mitochondria generate NADPH, but mutant IDHs consume NADPH. (v) ME1 located in the cytosol and ME2/3 located in mitochondria convert NADP⁺ into NADPH; (vi) the glutamine metabolism generates NADPH by GDH1/2 directly in mitochondria and generates aspartate that is transported into the cytosol for NADPH production depending on ME1. (vii) NNT catalyzes the transfer of hydride ions from NADH to NADP⁺ and produces NADPH to maintain the mitochondrial NADPH and the reverse-mode NNT that consumes NADPH may exist in cancer cells. (viii) The CPT1/2-mediated FAO generates acetyl CoA that enters the TCA cycle and contributes to NADPH production depending on IDHs and MEs. MPC mitochondirial pyruvate carrier, CTP citrate transport protein, OGC α-ketoglutarate-malate carrier, AGC aspartate–glutamate carrier