Homeostatic regulation of NAD(H) and NADP(H) in cells

Covarrubias AJ, Perrone R, Grozio A, Verdin E. NAD⁺ metabolism and its roles in cellular processes during ageing. Nat Rev Mol Cell Biol. 2021;22(2):119-141.

Ju HQ, Lin JF, Tian T, Xie D, Xu RH. NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications. Signal Transduct Targeted Ther. 2020;5(1):231.

Zapata-Pérez R, Wanders RJA, van Karnebeek CDM, Houtkooper RH. NAD⁺ homeostasis in human health and disease. EMBO Mol Med. 2021;13(7):e13943.

Xiao W, Wang RS, Handy DE, Loscalzo J. NAD(H) and NADP(H) redox couples and cellular energy metabolism. Antioxidants Redox Signal. 2018;28(3):251-272.

Navas LE, Carnero A. NAD⁺ metabolism, stemness, the immune response, and cancer. Signal Transduct Targeted Ther. 2021;6(1):2.

Houtkooper RH, Pirinen E, Auwerx J. Sirtuins as regulators of metabolism and healthspan. Nat Rev Mol Cell Biol. 2012;13(4):225-238.

Gupte R, Liu Z, Kraus WL. PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes. Genes Dev. 2017;31(2):101-126.

Ke Y, Zhang J, Lv X, Zeng X, Ba X. Novel insights into PARPs in gene expression: regulation of RNA metabolism. Cell Mol Life Sci. 2019;76(17):3283-3299.

Munnur D, Bartlett E, Mikolčević P, et al. Reversible ADP-ribosylation of RNA. Nucleic Acids Res. 2019;47(11):5658-5669.

Ray S, Abugable AA, Parker J, et al. A mechanism for oxidative damage repair at gene regulatory elements. Nature. 2022;609(7929):1038-1047.

Bilokapic S, Suskiewicz MJ, Ahel I, Halic M. Bridging of DNA breaks activates PARP2-HPF₁ to modify chromatin. Nature. 2020;585(7826):609-613.

Suskiewicz MJ, Zobel F, Ogden TEH, et al. HPF₁ completes the PARP active site for DNA damage-induced ADP-ribosylation. Nature. 2020;579(7800):598-602.

Takasawa S. CD38-cyclic ADP-ribose signal system in physiology, biochemistry, and pathophysiology. Int J Mol Sci. 2022;23(8):4306.

Lee HC. Mechanisms of calcium signaling by cyclic ADP-ribose and NAADP. Physiol Rev. 1997;77(4):1133-1164.

Malavasi F, Deaglio S, Funaro A, et al. Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. Physiol Rev. 2008;88(3):841-886.

Partida-Sánchez S, Cockayne DA, Monard S, et al. Cyclic ADP-ribose production by CD38 regulates intracellular calcium release, extracellular calcium influx, and chemotaxis in neutrophils and is required for bacterial clearance in vivo. Nat Med. 2001;7(11):1209-1216.

Partida-Sánchez S, Goodrich S, Kusser K, Oppenheimer N, Randall TD, Lund FE. Regulation of dendritic cell trafficking by the ADP-ribosyl cyclase CD38: impact on the development of humoral immunity. Immunity. 2004;20(3):279-291.

Lupu R, Menendez JA. Pharmacological inhibitors of fatty acid synthase (FASN): catalyzed endogenous fatty acid biogenesis: a new family of anti-cancer agents? Curr Pharmaceut Biotechnol. 2006;7(6):483-493.

Luo J, Yang H, Song BL. Mechanisms and regulation of cholesterol homeostasis. Nat Rev Mol Cell Biol. 2020;21(4):225-245.

Moreno-Sánchez R, Gallardo-Pérez JC, Rodríguez-Enríquez S, Saavedra E, Marín-Hernández Á. Control of the NADPH supply for oxidative stress handling in cancer cells. Free Radic Biol Med. 2017;112:149-161.

Palde PB, Carroll KS. A universal entropy-driven mechanism for thioredoxin-target recognition. Proc Natl Acad Sci U S A. 2015;112(26):7960-7965.

Pandey AV, Flück CE. NADPH P450 oxidoreductase: structure, function, and pathology of diseases. Pharmacol Ther. 2013;138(2):229-254.

Zhu J, Schwörer S, Berisa M, et al. Mitochondrial NADP(H) generation is essential for proline biosynthesis. Science. 2021;372(6545):968-972.

Tran DH, Kesavan R, Rion H, et al. Mitochondrial NADP⁺ is essential for proline biosynthesis during cell growth. Nat Metab. 2021;3(4):571-585.

Zheng Y, Lin TY, Lee G, et al. Mitochondrial one-carbon pathway supports cytosolic folate integrity in cancer cells. Cell. 2018;175(6):1546-1560.e17.

Cory JG, Sato A. Regulation of ribonucleotide reductase activity in mammalian cells. Mol Cell Biochem. 1983;53–54(1–2):257-266.

Panday A, Sahoo MK, Osorio D, Batra S. NADPH oxidases: an overview from structure to innate immunity-associated pathologies. Cell Mol Immunol. 2015;12(1):5-23.

Szanto I. NADPH oxidase 4 (NOX4) in cancer: linking redox signals to oncogenic metabolic adaptation. Int J Mol Sci. 2022;23(5):2702.

Winterbourn CC, Kettle AJ, Hampton MB. Reactive oxygen species and neutrophil function. Annu Rev Biochem. 2016;85:765-792.

Badawy AAB. Kynurenine pathway of tryptophan metabolism: regulatory and functional aspects. Int J Tryptophan Res. 2017;10:1178646917691938.

Braidy N, Berg J, Clement J, et al. Role of nicotinamide adenine dinucleotide and related precursors as therapeutic targets for age-related degenerative diseases: rationale, biochemistry, pharmacokinetics, and outcomes. Antioxidants Redox Signal. 2019;30(2):251-294.

Evans J, Wang TC, Heyes MP, Markey SP. LC/MS analysis of NAD biosynthesis using stable isotope pyridine precursors. Anal Biochem. 2002;306(2):197-203.

Xie N, Zhang L, Gao W, et al. NAD⁺ metabolism: pathophysiologic mechanisms and therapeutic potential. Signal Transduct Targeted Ther. 2020;5:227.

Reitman ZJ, Yan H. Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. J Natl Cancer Inst. 2010;102(13):932-941.

Asadi Shahmirzadi A, Edgar D, Liao CY, et al. Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice. Cell Metabol. 2020;32(3):447-456.e6.

Minárik P, Tomásková N, Kollárová M, Antalík M. Malate dehydrogenases: structure and function. Gen Physiol Biophys. 2002;21(3):257-265.

Yang SY, He XY, Schulz H. 3-Hydroxyacyl-CoA dehydrogenase and short chain 3-hydroxyacyl-CoA dehydrogenase in human health and disease. FEBS J. 2005;272(19):4874-4883.

Gu H, Chen C, Hao X, et al. MDH1-mediated malate-aspartate NADH shuttle maintains the activity levels of fetal liver hematopoietic stem cells. Blood. 2020;136(5):553-571.

Wang Y, Stancliffe E, Fowle-Grider R, et al. Saturation of the mitochondrial NADH shuttles drives aerobic glycolysis in proliferating cells. Mol Cell. 2022;82(17):3270-3283.e9.

Granchi C, Bertini S, Macchia M, Minutolo F. Inhibitors of lactate dehydrogenase isoforms and their therapeutic potentials. Curr Med Chem. 2010;17(7):672-697.

Fan J, Ye J, Kamphorst JJ, Shlomi T, Thompson CB, Rabinowitz JD. Quantitative flux analysis reveals folate-dependent NADPH production. Nature. 2014;510(7504):298-302.

Jiang P, Du W, Mancuso A, Wellen KE, Yang X. Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence. Nature. 2013;493(7434):689-693.

Lu YX, Ju HQ, Liu ZX, et al. Correction: ME1 regulates NADPH homeostasis to promote gastric cancer growth and metastasis. Cancer Res. 2019;79(14):3789.

Al-Khallaf H. Isocitrate dehydrogenases in physiology and cancer: biochemical and molecular insight. Cell Biosci. 2017;7:37.

Cai WF, Zhang C, Wu YQ, et al. Glutaminase GLS1 senses glutamine availability in a non-enzymatic manner triggering mitochondrial fusion. Cell Res. 2018;28(8):865-867.

Jiang P, Du W, Wu M. Regulation of the pentose phosphate pathway in cancer. Protein Cell. 2014;5(8):592-602.

Chen L, Zhang Z, Hoshino A, et al. NADPH production by the oxidative pentose-phosphate pathway supports folate metabolism. Nat Metab. 2019;1:404-415.

Wamelink MM, Struys EA, Jakobs C. The biochemistry, metabolism and inherited defects of the pentose phosphate pathway: a review. J Inherit Metab Dis. 2008;31(6):703-717.

Ralto KM, Rhee EP, Parikh SM. NAD⁺ homeostasis in renal health and disease. Nat Rev Nephrol. 2020;16(2):99-111.

Krupenko NI, Holmes RS, Tsybovsky Y, Krupenko SA. Aldehyde dehydrogenase homologous folate enzymes: evolutionary switch between cytoplasmic and mitochondrial localization. Chem Biol Interact. 2015;234:12-17.

Nilsson R, Jain M, Madhusudhan N, et al. Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer. Nat Commun. 2014;5:3128.

Ward NP, Kang YP, Falzone A, Boyle TA, DeNicola GM. Nicotinamide nucleotide transhydrogenase regulates mitochondrial metabolism in NSCLC through maintenance of Fe-S protein function. J Exp Med. 2020;217(6):e20191689.

Mhatre RM, Saslaw LD, Waravdekar VS. Effect of methotrexate on NAD kinase activity in leukaemic mice. Nature. 1967;214(5091):926-927.

Liu L, Su X, Quinn WJ, et al. Quantitative analysis of NAD synthesis-breakdown fluxes. Cell Metabol. 2018;27(5):1067-1080.e5.

Wickramaratne AC, Li L, Hopkins JB, Joachimiak LA, Green CB. The disordered amino terminus of the circadian enzyme nocturnin modulates its NADP(H) phosphatase activity by changing protein dynamics. Biochemistry. 2022. https://doi.org/10.1021/acs.biochem.2c00072.

Laothamatas I, Gao P, Wickramaratne A, et al. Spatiotemporal regulation of NADP(H) phosphatase Nocturnin and its role in oxidative stress response. Proc Natl Acad Sci USA. 2020;117(2):993-999.

Estrella MA, Du J, Chen L, et al. The metabolites NADP⁺ and NADPH are the targets of the circadian protein Nocturnin (Curled). Nat Commun. 2019;10(1):2367.

Ding CC, Rose J, Sun T, et al. MESH1 is a cytosolic NADPH phosphatase that regulates ferroptosis. Nat Metab. 2020;2(3):270-277.

Wang TA, Yu YV, Govindaiah G, et al. Circadian rhythm of redox state regulates excitability in suprachiasmatic nucleus neurons. Science. 2012;337(6096):839-842.

Reinke H, Asher G. Crosstalk between metabolism and circadian clocks. Nat Rev Mol Cell Biol. 2019;20(4):227-241.

Levine DC, Ramsey KM, Bass J. Circadian NAD(P)(H) cycles in cell metabolism. Semin Cell Dev Biol. 2022;126:15-26.

Yoshino J. Importance of NAMPT-mediated NAD-biosynthesis and NAD-dependent deacetylase SIRT1 in the crosstalk between circadian rhythm and metabolism. Nihon Rinsho. 2013;71(12):2187-2193.

Levine DC, Kuo HY, Hong HK, et al. NADH inhibition of SIRT1 links energy state to transcription during time-restricted feeding. Nat Metab. 2021;3(12):1621-1632.

Putker M, Crosby P, Feeney KA, et al. Mammalian circadian period, but not phase and amplitude, is robust against redox and metabolic perturbations. Antioxidants Redox Signal. 2018;28(7):507-520.

Hoxhaj G, Ben-Sahra I, Lockwood SE, et al. Direct stimulation of NADP⁺ synthesis through Akt-mediated phosphorylation of NAD kinase. Science. 2019;363(6431):1088-1092.

Shi F, Li Y, Li Y, Wang X. Molecular properties, functions, and potential applications of NAD kinases. Acta Biochim Biophys Sin. 2009;41(5):352-361 (Shanghai).

Ohashi K, Kawai S, Murata K. Identification and characterization of a human mitochondrial NAD kinase. Nat Commun. 2012;3:1248.

Lerner F, Niere M, Ludwig A, Ziegler M. Structural and functional characterization of human NAD kinase. Biochem Biophys Res Commun. 2001;288(1):69-74.

Mary C, Soflaee MH, Kesavan R, et al. Crystal structure of human NADK2 reveals a dimeric organization and active site occlusion by lysine acetylation. Mol Cell. 2022;82(17):3299-3311.e8.

Du J, Estrella M, Solorio-Kirpichyan K, Jeffrey PD, Korennykh A. Structure of human NADK2 reveals atypical assembly and regulation of NAD kinases from animal mitochondria. Proc Natl Acad Sci U S A. 2022;119(26):e2200923119.

Kim H, Fu Z, Yang Z, et al. The mitochondrial NAD kinase functions as a major metabolic regulator upon increased energy demand. Mol Metabol. 2022;64:101562.

Zhang K, Kim H, Fu Z, et al. Deficiency of the mitochondrial NAD kinase causes stress-induced hepatic steatosis in mice. Gastroenterology. 2018;154(1):224-237.

Bieganowski P, Seidle HF, Wojcik M, Brenner C. Synthetic lethal and biochemical analyses of NAD and NADH kinases in Saccharomyces cerevisiae establish separation of cellular functions. J Biol Chem. 2006;281(32):22439-22445.

Oka SI, Titus AS, Zablocki D, Sadoshima J. Molecular properties and regulation of NAD⁺ kinase (NADK). Redox Biol. 2023;59:102561.

Ivarsson R, Quintens R, Dejonghe S, et al. Redox control of exocytosis: regulatory role of NADPH, thioredoxin, and glutaredoxin. Diabetes. 2005;54(7):2132-2142.

Gray JP, Alavian KN, Jonas EA, Heart EA. NAD kinase regulates the size of the NADPH pool and insulin secretion in pancreatic β-cells. Am J Physiol Endocrinol Metab. 2012;303(2):E191-E199.

Xu M, Ding L, Liang J, et al. NAD kinase sustains lipogenesis and mitochondrial metabolismthrough fatty acid synthesis. Cell Rep. 2021;37(13):110157.

Ritterhoff J, Young S, Villet O, et al. Metabolic remodeling promotes cardiac hypertrophy by directing glucose to aspartate biosynthesis. Circ Res. 2020;126(2):182-196.

Matsuzawa-Nagata N, Takamura T, Ando H, et al. Increased oxidative stress precedes the onset of high-fat diet-induced insulin resistance and obesity. Metabolism. 2008;57(8):1071-1077.

De Ingeniis J, Ratnikov B, Richardson AD, et al. Functional specialization in proline biosynthesis of melanoma. PLoS One. 2012;7(9):e45190.

Dickinson ME, Flenniken AM, Ji X, et al. High-throughput discovery of novel developmental phenotypes. Nature. 2016;537(7621):508-514.

Pomerantz DJ, Ferdinandusse S, Cogan J, et al. Clinical heterogeneity of mitochondrial NAD kinase deficiency caused by a NADK2 start loss variant. Am J Med Genet. 2018;176(3):692-698.

Houten SM, Denis S, te Brinke H, et al. Mitochondrial NADP(H) deficiency due to a mutation in NADK2 causes dienoyl-CoA reductase deficiency with hyperlysinemia. Hum Mol Genet. 2014;23(18):5009-5016.

Ying W, Gao H, Dos Reis FCG, et al. miR-690, an exosomal-derived miRNA from M2-polarized macrophages, improves insulin sensitivity in obese mice. Cell Metabol. 2021;33(4):781-790.e5.

Love NR, Pollak N, Dölle C, et al. NAD kinase controls animal NADP biosynthesis and is modulated via evolutionarily divergent calmodulin-dependent mechanisms. Proc Natl Acad Sci U S A. 2015;112(5):1386-1391.

Gao H, Jin Z, Bandyopadhyay G, et al. miR-690 treatment causes decreased fibrosis and steatosis and restores specific Kupffer cell functions in NASH. Cell Metabol. 2022;34(7):978-990.e4.

Hoxhaj G, Manning BD. The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism. Nat Rev Cancer. 2020;20(2):74-88.

Hopkins BD, Goncalves MD, Cantley LC. Insulin-PI3K signalling: an evolutionarily insulated metabolic driver of cancer. Nat Rev Endocrinol. 2020;16(5):276-283.

Rabani R, Cossette C, Graham F, Powell WS. Protein kinase C activates NAD kinase in human neutrophils. Free Radic Biol Med. 2020;161:50-59.

Schild T, McReynolds MR, Shea C, et al. NADK is activated by oncogenic signaling to sustain pancreatic ductal adenocarcinoma. Cell Rep. 2021;35(11):109238.

Cao L, Huang C, Cui Zhou D, et al. Proteogenomic characterization of pancreatic ductal adenocarcinoma. Cell. 2021;184(19):5031-5052.e26.

Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487(7407):330-337.

Zhang Y, Xu Y, Lu W, et al. G6PD-mediated increase in de novo NADP⁺ biosynthesis promotes antioxidant defense and tumor metastasis. Sci Adv. 2022;8(29):eabo0404.

Zhang Y, Xu Y, Lu W, et al. Upregulation of antioxidant capacity and nucleotide precursor availability suffices for oncogenic transformation. Cell Metabol. 2021;33(1):94-109.e8.

Tsang YH, Dogruluk T, Tedeschi PM, et al. Functional annotation of rare gene aberration drivers of pancreatic cancer. Nat Commun. 2016;7:10500.

Zhang R. MNADK, a novel liver-enriched mitochondrion-localized NAD kinase. Biol Open. 2013;2(4):432-438.

Kawabata Y, Murata K, Kawai S. Significance of Ser-188 in human mitochondrial NAD kinase as determined by phosphomimetic and phosphoresistant amino-acid substitutions. Biochem Biophys Res Commun. 2015;468(4):691-695.

Caito S, Rajendrasozhan S, Cook S, et al. SIRT1 is a redox-sensitive deacetylase that is post-translationally modified by oxidants and carbonyl stress. Faseb J. 2010;24(9):3145-3159.

Kim H, Mendez R, Zheng Z, et al. Liver-enriched transcription factor CREBH interacts with peroxisome proliferator-activated receptor α to regulate metabolic hormone FGF₂₁. Endocrinology. 2014;155(3):769-782.

Ahn BH, Kim HS, Song S, et al. A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc Natl Acad Sci U S A. 2008;105(38):14447-14452.

Sun D, Lee G, Lee JH, et al. A metazoan ortholog of SpoT hydrolyzes ppGpp and functions in starvation responses. Nat Struct Mol Biol. 2010;17(10):1188-1194.

Liu CC, Gebicki JM. Intracellular GSH and ascorbate inhibit radical-induced protein chain peroxidation in HL-60 cells. Free Radic Biol Med. 2012;52(2):420-426.

Stubblefield JJ, Gao P, Kilaru G, Mukadam B, Terrien J, Green CB. Temporal control of metabolic amplitude by nocturnin. Cell Rep. 2018;22(5):1225-1235.

Green CB, Douris N, Kojima S, et al. Loss of Nocturnin, a circadian deadenylase, confers resistance to hepatic steatosis and diet-induced obesity. Proc Natl Acad Sci U S A. 2007;104(23):9888-9893.

Neve EPA, Ingelman-Sundberg M. Intracellular transport and localization of microsomal cytochrome P450. Anal Bioanal Chem. 2008;392(6):1075-1084.

Nakahata Y, Sahar S, Astarita G, Kaluzova M, Sassone-Corsi P. Circadian control of the NAD⁺ salvage pathway by CLOCK-SIRT1. Science. 2009;324(5927):654-657.

Rutter J, Reick M, Wu LC, McKnight SL. Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors. Science. 2001;293(5529):510-514.

Ramsey KM, Yoshino J, Brace CS, et al. Circadian clock feedback cycle through NAMPT-mediated NAD⁺ biosynthesis. Science. 2009;324(5927):651-654.

Bellet MM, Nakahata Y, Boudjelal M, et al. Pharmacological modulation of circadian rhythms by synthetic activators of the deacetylase SIRT1. Proc Natl Acad Sci U S A. 2013;110(9):3333-3338.

Koronowski KB, Kinouchi K, Welz PS, et al. Defining the independence of the liver circadian clock. Cell. 2019;177(6):1448-1462.e14.

Laval-Martin DL, Carré IA, Barbera SJ, Edmunds Jr LN. Circadian variations in the affinities of NAD kinase and NADP phosphatase for their substrates, NAD⁺ and NADP⁺, in dividing and nondividing cells of the achlorophyllous ZC mutant of Euglena gracilis Klebs (strain Z). Chronobiol Int. 1990;7(2):99-105.

Asher G, Gatfield D, Stratmann M, et al. SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell. 2008;134(2):317-328.

Nakahata Y, Kaluzova M, Grimaldi B, et al. The NAD⁺-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell. 2008;134(2):329-340.

Sahar S, Nin V, Barbosa MT, Chini EN, Sassone-Corsi P. Altered behavioral and metabolic circadian rhythms in mice with disrupted NAD⁺ oscillation. Aging. 2011;3(8):794-802.

Audrito V, Messana VG, Deaglio S. NAMPT and NAPRT: two metabolic enzymes with key roles in inflammation. Front Oncol. 2020;10:358.

Garten A, Petzold S, Körner A, Imai SI, Kiess W. Nampt: linking NAD biology, metabolism and cancer. Trends Endocrinol Metabol. 2009;20(3):130-138.

Fletcher RS, Ratajczak J, Doig CL, et al. Nicotinamide riboside kinases display redundancy in mediating nicotinamide mononucleotide and nicotinamide riboside metabolism in skeletal muscle cells. Mol Metabol. 2017;6(8):819-832.

Bieganowski P, Brenner C. Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD⁺ in fungi and humans. Cell. 2004;117(4):495-502.

Pollak N, Dölle C, Ziegler M. The power to reduce: pyridine nucleotides: small molecules with a multitude of functions. Biochem J. 2007;402(2):205-218.

Ying W. NAD⁺/NADH and NADP⁺/NADPH in cellular functions and cell death: regulation and biological consequences. Antioxidants Redox Signal. 2008;10(2):179-206.

Zhang T, Berrocal JG, Frizzell KM, et al. Enzymes in the NAD⁺ salvage pathway regulate SIRT1 activity at target gene promoters. J Biol Chem. 2009;284(30):20408-20417.

Yaku K, Okabe K, Hikosaka K, Nakagawa T. NAD metabolism in cancer therapeutics. Front Oncol. 2018;8:622.

Xie H, Lei Y, Mao Y, et al. FK866 inhibits colorectal cancer metastasis by reducing NAD⁺ levels in cancer-associated fibroblasts. Genes Genomics. 2022;44(12):1531-1541.

Wei Y, Xiang H, Zhang W. Review of various NAMPT inhibitors for the treatment of cancer. Front Pharmacol. 2022;13:970553.

Sharif T, Ahn DG, Liu RZ, et al. The NAD⁺ salvage pathway modulates cancer cell viability via p73. Cell Death Differ. 2016;23(4):669-680.

Galli U, Travelli C, Massarotti A, et al. Medicinal chemistry of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. J Med Chem. 2013;56(16):6279-6296.

Garten A, Schuster S, Penke M, Gorski T, de Giorgis T, Kiess W. Physiological and pathophysiological roles of NAMPT and NAD metabolism. Nat Rev Endocrinol. 2015;11(9):535-546.

Bi TQ, Che XM, Liao XH, et al. Overexpression of Nampt in gastric cancer and chemopotentiating effects of the Nampt inhibitor FK866 in combination with fluorouracil. Oncol Rep. 2011;26(5):1251-1257.

Heske CM. Beyond energy metabolism: exploiting the additional roles of NAMPT for cancer therapy. Front Oncol. 2019;9:1514.

Fratta S, Biniecka P, Moreno-Vargas AJ, et al. Synthesis and structure-activity relationship of new nicotinamide phosphoribosyltransferase inhibitors with antitumor activity on solid and haematological cancer. Eur J Med Chem. 2023;250:115170.

Holen K, Saltz LB, Hollywood E, Burk K, Hanauske AR. The pharmacokinetics, toxicities, and biologic effects of FK866, a nicotinamide adenine dinucleotide biosynthesis inhibitor. Invest N Drugs. 2008;26(1):45-51.

Bogan KL, Brenner C. Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition. Annu Rev Nutr. 2008;28:115-130.

Cantó C, Menzies KJ, Auwerx J. NAD⁺ metabolism and the control of energy homeostasis: a balancing act between mitochondria and the nucleus. Cell Metabol. 2015;22(1):31-53.

Zhao M, Yao P, Mao Y, et al. Malic enzyme 2 maintains protein stability of mutant p53 through 2-hydroxyglutarate. Nat Metab. 2022;4(2):225-238.

Notarangelo G, Spinelli JB, Perez EM, et al. Oncometabolite d-2HG alters T cell metabolism to impair CD8⁺ T cell function. Science. 2022;377(6614):1519-1529.

Tedeschi PM, Bansal N, Kerrigan JE, Abali EE, Scotto KW, Bertino JR. NAD⁺ kinase as a therapeutic target in cancer. Clin Cancer Res. 2016;22(21):5189-5195.

Tedeschi PM, Lin H, Gounder M, et al. Suppression of cytosolic NADPH pool by thionicotinamide increases oxidative stress and synergizes with chemotherapy. Mol Pharmacol. 2015;88(4):720-727.

De Braekeleer E, Hsu J, Hervieu C, et al. The nucleotide kinase Nadk is required for ROS detoxification and constitutes a metabolic vulnerability of NOTCH1-driven T-ALL. Blood. 2018;132(suppl 1), 2615-2615.

Kerk SA, Papagiannakopoulos T, Shah YM, Lyssiotis CA. Metabolic networks in mutant KRAS-driven tumours: tissue specificities and the microenvironment. Nat Rev Cancer. 2021;21(8):510-525.

Hsieh YC, Tedeschi P, Adebisi Lawal R, et al. Enhanced degradation of dihydrofolate reductase through inhibition of NAD kinase by nicotinamide analogs. Mol Pharmacol. 2013;83(2):339-353.

Nogueira V, Hay N. Molecular pathways: reactive oxygen species homeostasis in cancer cells and implications for cancer therapy. Clin Cancer Res. 2013;19(16):4309-4314.

Zhou CC, Yang X, Hua X, et al. Hepatic NAD⁺ deficiency as a therapeutic target for non-alcoholic fatty liver disease in ageing. Br J Pharmacol. 2016;173(15):2352-2368.

Sun T, Ding CC, Zhang Y, et al. MESH1 knockdown triggers proliferation arrest through TAZ repression. Cell Death Dis. 2022;13(3):221.

Abshire ET, Hughes KL, Diao R, et al. Differential processing and localization of human Nocturnin controls metabolism of mRNA and nicotinamide adenine dinucleotide cofactors. J Biol Chem. 2020;295(44):15112-15133.

Luongo TS, Eller JM, Lu MJ, et al. SLC25A51 is a mammalian mitochondrial NAD⁺ transporter. Nature. 2020;588(7836):174-179.

Kory N, Uit de Bos J, van der Rijt S, et al. MCART1/SLC25A51 is required for mitochondrial NAD transport. Sci Adv. 2020;6(43):eabe5310.

Girardi E, Agrimi G, Goldmann U, et al. Epistasis-driven identification of SLC25A51 as a regulator of human mitochondrial NAD import. Nat Commun. 2020;11(1):6145.