Glutaminolysis is a Potential Therapeutic Target for Kidney Diseases

References

• Altman BJ, Stine ZE, Dang CV. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer. 2016;16(10):619–634. doi:10.1038/nrc.2016.71
   PubMed Web of Science ®Google Scholar
• Cruzat V, Macedo Rogero M, Noel Keane K, Curi R, Newsholme P. Glutamine: metabolism and immune function, supplementation and clinical translation. Nutrients. 2018;10(11). doi:10.3390/nu10111564
   PubMed Web of Science ®Google Scholar
• Yang L, Venneti S, Nagrath D. Glutaminolysis: a hallmark of cancer metabolism. Annu Rev Biomed Eng. 2017;19:163–194. doi:10.1146/annurev-bioeng-071516-044546
   PubMed Web of Science ®Google Scholar
• Cooper AJ, Shurubor YI, Dorai T, et al. ω-Amidase: an underappreciated, but important enzyme in L-glutamine and L-asparagine metabolism; relevance to sulfur and nitrogen metabolism, tumor biology and hyperammonemic diseases. Amino Acids. 2016;48(1):1–20. doi:10.1007/s00726-015-2061-7
   PubMed Web of Science ®Google Scholar
• Guo L, Chen S, Ou L, Li S, Ye ZN, Liu HF. Disrupted alpha-ketoglutarate homeostasis: understanding kidney diseases from the view of metabolism and beyond. Diabetes Metab Syndr Obes. 2022;15:1961–1974. doi:10.2147/dmso.S369090
   PubMed Web of Science ®Google Scholar
• Xiang Z, Bai L, Zhou JQ, et al. Epigenetic regulation of IPF fibroblast phenotype by glutaminolysis. Mol Metab. 2023;67:101655. doi:10.1016/j.molmet.2022.101655
   PubMed Web of Science ®Google Scholar
• Choudhury D, Rong N, Ikhapoh I, et al. Inhibition of glutaminolysis restores mitochondrial function in senescent stem cells. Cell Rep. 2022;41(9):111744. doi:10.1016/j.celrep.2022.111744
   PubMed Web of Science ®Google Scholar
• Yiew NKH, Vazquez JH, Martino MR, et al. Hepatic pyruvate and alanine metabolism are critical and complementary for maintenance of antioxidant capacity and resistance to oxidative insult. Mol Metab. 2023;77:101808. doi:10.1016/j.molmet.2023.101808
   PubMed Web of Science ®Google Scholar
• Weiner ID, Hamm LL. Molecular mechanisms of renal ammonia transport. Annu Rev Physiol. 2007;69:317–340. doi:10.1146/annurev.physiol.69.040705.142215
   PubMed Web of Science ®Google Scholar
• Antunes D, Gonçalves SM, Matzaraki V, et al. Glutamine metabolism supports the functional activity of immune cells against aspergillus fumigatus. Microbiol Spectr. 2023;11(1):e0225622. doi:10.1128/spectrum.02256-22
   PubMed Web of Science ®Google Scholar
• Takahashi S, Saegusa J, Sendo S, et al. Glutaminase 1 plays a key role in the cell growth of fibroblast-like synoviocytes in rheumatoid arthritis. Arthritis Res Ther. 2017;19(1):76. doi:10.1186/s13075-017-1283-3
   PubMedGoogle Scholar
• Kono M, Yoshida N, Maeda K, Suárez-Fueyo A, Kyttaris VC, Tsokos GC. Glutaminase 1 inhibition reduces glycolysis and ameliorates lupus-like disease in mrl/lpr mice and experimental autoimmune encephalomyelitis. Arthritis Rheumatol. 2019;71(11):1869–1878. doi:10.1002/art.41019
   PubMed Web of Science ®Google Scholar
• Szeliga M, Bogacińska-Karaś M, Kuźmicz K, Rola R, Albrecht J. Downregulation of GLS2 in glioblastoma cells is related to DNA hypermethylation but not to the p53 status. Mol, Carcinog. 2016;55(9):1309–1316. doi:10.1002/mc.22372
   PubMed Web of Science ®Google Scholar
• Zhong G, Su S, Li J, et al. Activation of Piezo1 promotes osteogenic differentiation of aortic valve interstitial cell through YAP-dependent glutaminolysis. Sci Adv. 2023;9(22):eadg0478. doi:10.1126/sciadv.adg0478
   PubMed Web of Science ®Google Scholar
• Zhang T, Cui Y, Wu Y, et al. Mitochondrial GCN5L1 regulates glutaminase acetylation and hepatocellular carcinoma. Clin Transl Med. 2022;12(5):e852. doi:10.1002/ctm2.852
   PubMed Web of Science ®Google Scholar
• Cai Y, Tian B, Deng Y, et al. Glutamine metabolism promotes renal fibrosis through regulation of mitochondrial energy generation and mitochondrial fission. Int J Biol Sci. 2024;20(3):987–1003. doi:10.7150/ijbs.89960
   PubMed Web of Science ®Google Scholar
• Hu J, Zhang Z, Hu H, et al. LRH-1 activation alleviates diabetes-induced podocyte injury by promoting GLS2-mediated glutaminolysis. Cell Prolif. 2023;56(11):e13479. doi:10.1111/cpr.13479
   PubMed Web of Science ®Google Scholar
• Lee K, Thompson EA, Gharaie S, et al. T cell metabolic reprogramming in acute kidney injury and protection by glutamine blockade. JCI Insight. 2023;8(12). doi:10.1172/jci.insight.160345
   Web of Science ®Google Scholar
• Kono M, Yoshida N, Maeda K, Tsokos GC. Transcriptional factor ICER promotes glutaminolysis and the generation of Th17 cells. Proc Natl Acad Sci U S A. 2018;115(10):2478–2483. doi:10.1073/pnas.171123045125
   PubMed Web of Science ®Google Scholar
• Sharma A, Lavie CJ, Sharma SK, et al. Duration of dual antiplatelet therapy after drug-eluting stent implantation in patients with and without acute coronary syndrome: a systematic review of randomized controlled trials. Mayo Clin Proc. 2016;91(8):1084–1093. doi:10.1016/j.mayocp.2016.06.004
   PubMed Web of Science ®Google Scholar
• Fu Q, Xu L, Wang Y, et al. Tumor-associated macrophage-derived interleukin-23 interlinks kidney cancer glutamine addiction with immune evasion. Eur Urol. 2019;75(5):752–763. doi:10.1016/j.eururo.2018.09.030
   PubMed Web of Science ®Google Scholar
• Grayson PC, Eddy S, Taroni JN, et al. Metabolic pathways and immunometabolism in rare kidney diseases. Ann Rheum Dis. 2018;77(8):1226–1233. doi:10.1136/annrheumdis-2017-212935
   PubMed Web of Science ®Google Scholar
• Flowers EM, Sudderth J, Zacharias L, et al. Lkb1 deficiency confers glutamine dependency in polycystic kidney disease. Nat Commun. 2018;9(1):814. doi:10.1038/s41467-018-03036-y
   PubMedGoogle Scholar
• Kühtreiber WM, Takahashi H, Keefe RC, et al. BCG vaccinations upregulate myc, a central switch for improved glucose metabolism in diabetes. iScience. 2020;23(5):101085. doi:10.1016/j.isci.2020.101085
   PubMed Web of Science ®Google Scholar
• Wise DR, DeBerardinis RJ, Mancuso A, et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci U S A. 2008;105(48):18782–18787. doi:10.1073/pnas.0810199105
   PubMed Web of Science ®Google Scholar
• Gao P, Tchernyshyov I, Chang TC, et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature. 2009;458:762–5. doi:10.1038/nature07823
   PubMed Web of Science ®Google Scholar
• Kim JH, Lee KJ, Seo Y, et al. Effects of metformin on colorectal cancer stem cells depend on alterations in glutamine metabolism. Sci Rep. 2018;8(1):409. doi:10.1038/s41598-017-18762-4
   PubMedGoogle Scholar
• Munksgaard Thorén M, Vaapil M, Staaf J, et al. Myc-induced glutaminolysis bypasses HIF-driven glycolysis in hypoxic small cell lung carcinoma cells. Oncotarget. 2017;8(30):48983–48995. doi:10.18632/oncotarget.16904
   PubMedGoogle Scholar
• Wu H, Li Z, Yang P, Zhang L, Fan Y, Li Z. PKM2 depletion induces the compensation of glutaminolysis through β-catenin/c-Myc pathway in tumor cells. Cell Signal. 2014;26(11):2397–2405. doi:10.1016/j.cellsig.2014.07.024
   PubMed Web of Science ®Google Scholar
• Haikala HM, Marques E, Turunen M, Klefström J. Myc requires RhoA/SRF to reprogram glutamine metabolism. Small GTPases. 2018;9(3):274–282. doi:10.1080/21541248.2016.1224287
   PubMedGoogle Scholar
• Shroff EH, Eberlin LS, Dang VM, et al. MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism. Proc Natl Acad Sci U S A. 2015;112(21):6539–6544. doi:10.1073/pnas.1507228112
   PubMed Web of Science ®Google Scholar
• Freire WB. Hemoglobin as a predictor of response to iron therapy and its use in screening and prevalence estimates. Am J Clin Nutr. 1989;50(6):1442–1449. doi:10.1093/ajcn/50.6.1442
   PubMed Web of Science ®Google Scholar
• Białopiotrowicz E, Noyszewska-Kania M, Kachamakova-Trojanowska N, et al. Serine biosynthesis pathway supports MYC-miR-494-EZH2 feed-forward circuit necessary to maintain metabolic and epigenetic reprogramming of Burkitt lymphoma cells. Cancers (Basel). 2020;12(3):580. doi:10.3390/cancers12030580
   PubMed Web of Science ®Google Scholar
• Habshi T, Shelke V, Kale A, Lech M, Gaikwad AB. Hippo signaling in acute kidney injury to chronic kidney disease transition: current understandings and future targets. Drug Discov Today. 2023;28(8):103649. doi:10.1016/j.drudis.2023.103649
   PubMed Web of Science ®Google Scholar
• Du K, Hyun J, Premont RT, et al. Hedgehog-YAP signaling pathway regulates glutaminolysis to control activation of hepatic stellate cells. Gastroenterology. 2018;154(5):1465–1479.e13. doi:10.1053/j.gastro.2017.12.022
   PubMed Web of Science ®Google Scholar
• Bertero T, Oldham WM, Cottrill KA, et al. Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension. J Clin Invest. 2016;126(9):3313–3335. doi:10.1172/jci86387
   PubMed Web of Science ®Google Scholar
• Cox AG, Hwang KL, Brown KK, et al. Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth. Nat Cell Biol. 2016;18(8):886–896. doi:10.1038/ncb3389
   PubMed Web of Science ®Google Scholar
• Yang CS, Stampouloglou E, Kingston NM, Zhang L, Monti S, Varelas X. Glutamine-utilizing transaminases are a metabolic vulnerability of TAZ/YAP-activated cancer cells. EMBO Rep. 2018;19(6). doi:10.15252/embr.201643577
   Web of Science ®Google Scholar
• Choi S, Hong SP, Bae JH, et al. Hyperactivation of YAP/TAZ drives alterations in mesangial cells through stabilization of N-myc in diabetic nephropathy. J Am Soc Nephrol. 2023;34(5):809–828. doi:10.1681/asn.0000000000000075
   PubMed Web of Science ®Google Scholar
• Vallée A, Lecarpentier Y, Vallée JN. The Key Role of the WNT/β-catenin pathway in metabolic reprogramming in cancers under normoxic conditions. Cancers (Basel). 2021;13(21). doi:10.3390/cancers13215557
   Web of Science ®Google Scholar
• El-Sahli S, Xie Y, Wang L, Liu S. Wnt signaling in cancer metabolism and immunity. Cancers (Basel). 2019;11(7):904. doi:10.3390/cancers11070904
   PubMed Web of Science ®Google Scholar
• Cadoret A, Ovejero C, Terris B, et al. New targets of beta-catenin signaling in the liver are involved in the glutamine metabolism. Oncogene. 2002;21(54):8293–8301. doi:10.1038/sj.onc.1206118
   PubMed Web of Science ®Google Scholar
• Zhou B, Magana L, Hong Z, et al. The angiocrine Rspondin3 instructs interstitial macrophage transition via metabolic-epigenetic reprogramming and resolves inflammatory injury. Nat Immunol. 2020;21(11):1430–1443. doi:10.1038/s41590-020-0764-8
   PubMed Web of Science ®Google Scholar
• Wong CC, Xu J, Bian X, et al. In colorectal cancer cells with mutant KRAS, SLC25A22-mediated glutaminolysis reduces DNA Demethylation to Increase WNT signaling, stemness, and drug resistance. Gastroenterology. 2020;159(6):2163–2180.e6. doi:10.1053/j.gastro.2020.08.016
   PubMed Web of Science ®Google Scholar
• Liao J, Liu PP, Hou G, et al. Regulation of stem-like cancer cells by glutamine through β-catenin pathway mediated by redox signaling. Mol Cancer. 2017;16(1):51. doi:10.1186/s12943-017-0623-x
   PubMed Web of Science ®Google Scholar
• Brunialti E, Rizzi N, Pinto-Costa R, et al. Design and validation of a reporter mouse to study the dynamic regulation of TFEB and TFE3 activity through in vivo imaging techniques. Autophagy. 2024:1–16. doi:10.1080/15548627.2024.2334111
   Web of Science ®Google Scholar
• Ariano C, Costanza F, Akman M, et al. TFEB inhibition induces melanoma shut-down by blocking the cell cycle and rewiring metabolism. Cell Death Dis. 2023;14(5):314. doi:10.1038/s41419-023-05828-7
   PubMed Web of Science ®Google Scholar
• Kim JH, Lee J, Cho YR, et al. TFEB supports pancreatic cancer growth through the transcriptional regulation of glutaminase. Cancers (Basel). 2021;13(3). doi:10.3390/cancers13030483
   Web of Science ®Google Scholar
• Nowis D, Malenda A, Furs K, et al. Statins impair glucose uptake in human cells. BMJ Open Diabetes Res Care. 2014;2(1):e000017. doi:10.1136/bmjdrc-2014-000017
   PubMedGoogle Scholar
• Durán RV, Oppliger W, Robitaille AM, et al. Glutaminolysis activates Rag-mTORC1 signaling. Mol Cell. 2012;47(3):349–358. doi:10.1016/j.molcel.2012.05.043
   PubMed Web of Science ®Google Scholar
• Bodineau C, Tomé M, Courtois S, et al. Two parallel pathways connect glutamine metabolism and mTORC1 activity to regulate glutamoptosis. Nat Commun. 2021;12(1):4814. doi:10.1038/s41467-021-25079-4
   PubMed Web of Science ®Google Scholar
• Csibi A, Fendt SM, Li C, et al. The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell. 2013;153(4):840–854. doi:10.1016/j.cell.2013.04.023
   PubMed Web of Science ®Google Scholar
• Csibi A, Lee G, Yoon SO, et al. The mTORC1/S6K1 pathway regulates glutamine metabolism through the eIF4B-dependent control of c-Myc translation. Curr Biol. 2014;24(19):2274–2280. doi:10.1016/j.cub.2014.08.007
   PubMed Web of Science ®Google Scholar
• Xuan C, Cui H, Jin Z, et al. Glutamine ameliorates hyperoxia-induced hippocampal damage by attenuating inflammation and apoptosis via the MKP-1/MAPK signaling pathway in neonatal rats. Front Pharmacol. 2023;14:1096309. doi:10.3389/fphar.2023.1096309
   PubMed Web of Science ®Google Scholar
• Jeong SY, Im YN, Youm JY, Lee HK, Im SY. l-glutamine attenuates DSS-induced colitis via induction of MAPK phosphatase-1. Nutrients. 2018;10(3):288. doi:10.3390/nu10030288
   PubMed Web of Science ®Google Scholar
• Ayush O, Jin ZW, Kim HK, Shin YR, Im SY, Lee HK. Glutamine up-regulates MAPK phosphatase-1 induction via activation of Ca(2+)→ ERK cascade pathway. Biochem Biophys Rep. 2016;7:10–19. doi:10.1016/j.bbrep.2016.05.011
   PubMedGoogle Scholar
• Lee CH, Kim HK, Jeong JS, et al. Mechanism of glutamine inhibition of cytosolic phospholipase a2 (cPLA2): evidence of physical interaction between glutamine-Induced mitogen-activated protein kinase phosphatase-1 and cPLA2. Clin Exp Immunol. 2015;180(3):571–580. doi:10.1111/cei.12585
   PubMed Web of Science ®Google Scholar
• Ko HM, Oh SH, Bang HS, et al. Glutamine protects mice from lethal endotoxic shock via a rapid induction of MAPK phosphatase-1. J Immunol. 2009;182(12):7957–7962. doi:10.4049/jimmunol.0900043
   PubMed Web of Science ®Google Scholar
• Ayush O, Lee CH, Kim HK, Im SY, Cho BH, Lee HK. Glutamine suppresses DNFB-induced contact dermatitis by deactivating p38 mitogen-activated protein kinase via induction of MAPK phosphatase-1. J Invest Dermatol. 2013;133(3):723–731. doi:10.1038/jid.2012.373
   PubMed Web of Science ®Google Scholar
• Carey BW, Finley LW, Cross JR, Allis CD, Thompson CB. Intracellular α-ketoglutarate maintains the pluripotency of embryonic stem cells. Nature. 2015;518(7539):413–6. doi:10.1038/nature13981
   PubMed Web of Science ®Google Scholar
• Tran TQ, Hanse EA, Habowski AN, et al. α-Ketoglutarate attenuates Wnt signaling and drives differentiation in colorectal cancer. Nat Cancer. 2020;1(3):345–358. doi:10.1038/s43018-020-0035-5
   PubMedGoogle Scholar
• Dang L, White DW, Gross S, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462:7274):739–44. doi:10.1038/nature08617
   Web of Science ®Google Scholar
• Seltzer MJ, Bennett BD, Joshi AD, et al. Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1. Cancer Res. 2010;70(22):8981–8987. doi:10.1158/0008-5472.Can-10-1666
   PubMed Web of Science ®Google Scholar
• Chen PR, Lucas CG, Spate LD, Prather RS. Glutaminolysis is involved in the activation of mTORC1 in in vitro-produced porcine embryos. Mol Reprod Dev. 2021;88(7):490–499. doi:10.1002/mrd.23516
   PubMed Web of Science ®Google Scholar
• Torrino S, Grasset EM, Audebert S, et al. Mechano-induced cell metabolism promotes microtubule glutamylation to force metastasis. Cell Metab. 2021;33(7):1342–1357.e10. doi:10.1016/j.cmet.2021.05.009
   PubMed Web of Science ®Google Scholar
• Zhao S, Wang JM, Yan J, et al. BAG3 promotes autophagy and glutaminolysis via stabilizing glutaminase. Cell Death Dis. 2019;10(4):284. doi:10.1038/s41419-019-1504-6
   PubMedGoogle Scholar
• Li X, Yang Y, Zhang B, et al. Lactate metabolism in human health and disease. Signal Transduct Target Ther. 2022;7(1):305. doi:10.1038/s41392-022-01151-3
   PubMed Web of Science ®Google Scholar
• Han T, Wang P, Wang Y, et al. FAIM regulates autophagy through glutaminolysis in lung adenocarcinoma. Autophagy. 2022;18(6):1416–1432. doi:10.1080/15548627.2021.1987672
   PubMed Web of Science ®Google Scholar
• Swamy M, Pathak S, Grzes KM, et al. Glucose and glutamine fuel protein O-GlcNAcylation to control T cell self-renewal and malignancy. Nat Immunol. 2016;17(6):712–720. doi:10.1038/ni.3439
   PubMed Web of Science ®Google Scholar
• Tung MC, Lin PL, Wang YC, et al. Mutant p53 confers chemoresistance in non-small cell lung cancer by upregulating Nrf2. Oncotarget. 2015;6(39):41692–41705. doi:10.18632/oncotarget.6150
   PubMedGoogle Scholar
• Walerych D, Lisek K, Sommaggio R, et al. Proteasome machinery is instrumental in a common gain-of-function program of the p53 missense mutants in cancer. Nat Cell Biol. 2016;18(8):897–909. doi:10.1038/ncb3380
   PubMed Web of Science ®Google Scholar
• Chen D, Tavana O, Chu B, et al. NRF2 Is a Major Target of ARF in p53-Independent Tumor Suppression. Mol Cell. 2017;68(1):224–232.e4. doi:10.1016/j.molcel.2017.09.009
   PubMed Web of Science ®Google Scholar
• Thomas K, Zondler L, Ludwig N, et al. Glutamine prevents acute kidney injury by modulating oxidative stress and apoptosis in tubular epithelial cells. JCI Insight. 2022;7(21). doi:10.1172/jci.insight.163161
   Web of Science ®Google Scholar
• Yuan L, Sheng X, Clark LH, et al. Glutaminase inhibitor compound 968 inhibits cell proliferation and sensitizes paclitaxel in ovarian cancer. Am J Transl Res. 2016;8(10):4265–4277.
   PubMed Web of Science ®Google Scholar
• Yuan L, Sheng X, Willson AK, et al. Glutamine promotes ovarian cancer cell proliferation through the mTOR/S6 pathway. Endocr Relat Cancer. 2015;22(4):577–591. doi:10.1530/erc-15-0192
   PubMed Web of Science ®Google Scholar
• Rinschen MM, Harder JL, Carter-Timofte ME, et al. VPS34-dependent control of apical membrane function of proximal tubule cells and nutrient recovery by the kidney. Sci Signal. 2022;15(762):eabo7940. doi:10.1126/scisignal.abo7940
   PubMed Web of Science ®Google Scholar
• Oberkersch RE, Pontarin G, Astone M, et al. Aspartate metabolism in endothelial cells activates the mTORC1 pathway to initiate translation during angiogenesis. Dev Cell. 2022;57(10):1241–1256.e8. doi:10.1016/j.devcel.2022.04.018
   PubMed Web of Science ®Google Scholar
• Basso PJ, Andrade-Oliveira V, Câmara NOS. Targeting immune cell metabolism in kidney diseases. Nat Rev Nephrol. 2021;17(7):465–480. doi:10.1038/s41581-021-00413-7
   PubMed Web of Science ®Google Scholar
• Xue X, Zeng X, Wu X, Mu K, Dai Y, Wei Z. SIRT4 protects against intestinal fibrosis by facilitating GLS1 degradation. Matrix Biol. 2023;122:33–45. doi:10.1016/j.matbio.2023.08.001
   PubMed Web of Science ®Google Scholar
• Xiong J, Luu TTT, Venkatachalam K, Du G, Zhu MX. Glutamine produces ammonium to tune lysosomal pH and regulate lysosomal function. Cells. 2022;12(1). doi:10.3390/cells12010080
   Web of Science ®Google Scholar
• Gibb AA, Huynh AT, Gaspar RB, et al. Glutamine uptake and catabolism is required for myofibroblast formation and persistence. J Mol Cell Cardiol. 2022;172:78–89. doi:10.1016/j.yjmcc.2022.08.002
   PubMed Web of Science ®Google Scholar
• Jiang Q, Qiu Y, Kurland IJ, et al. Glutamine is required for M1-like polarization of macrophages in response to mycobacterium tuberculosis infection. mBio. 2022;13(4):e0127422. doi:10.1128/mbio.01274-22
   PubMed Web of Science ®Google Scholar
• Quinteros SL, von Krusenstiern E, Snyder NW, Tanaka A, O’Brien B, Donnelly S. The helminth derived peptide FhHDM-1 redirects macrophage metabolism towards glutaminolysis to regulate the pro-inflammatory response. Front Immunol. 2023;14:1018076. doi:10.3389/fimmu.2023.1018076
   PubMed Web of Science ®Google Scholar
• Liu JQ, Geng XR, Hu TY, et al. Glutaminolysis is required in maintaining immune regulatory functions in B cells. Mucosal Immunol. 2022;15(2):268–278. doi:10.1038/s41385-021-00481-9
   PubMed Web of Science ®Google Scholar
• Choi SC, Li W, Zhang X, et al. Pharmacologically inferred glycolysis and glutaminolysis requirement of b cells in lupus-prone mice. J Immunol. 2022;208(9):2098–2108. doi:10.4049/jimmunol.2100356
   PubMed Web of Science ®Google Scholar
• Lombardi AA, Gibb AA, Arif E, et al. Mitochondrial calcium exchange links metabolism with the epigenome to control cellular differentiation. Nat Commun. 2019;10(1):4509. doi:10.1038/s41467-019-12103-x
   PubMedGoogle Scholar
• Johmura Y, Yamanaka T, Omori S, et al. Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders. Science. 2021;371:6526):265–270. doi:10.1126/science.abb5916
   Web of Science ®Google Scholar
• Zhang Y, Huang Z, Han W, et al. Glutamine suppresses senescence and promotes autophagy through glycolysis inhibition-mediated AMPKα lactylation in intervertebral disc degeneration. Commun Biol. 2024;7(1):325. doi:10.1038/s42003-024-06000-3
   PubMed Web of Science ®Google Scholar
• Huang Y, Wang B, Hassounah F, et al. The impact of senescence on muscle wasting in chronic kidney disease. J Cachexia, Sarcopenia Muscle. 2023;14(1):126–141. doi:10.1002/jcsm.13112
   PubMedGoogle Scholar
• Pena MJ, Lambers Heerspink HJ, Hellemons ME, et al. Urine and plasma metabolites predict the development of diabetic nephropathy in individuals with Type 2 diabetes mellitus. Diabet Med. 2014;31(9):1138–1147. doi:10.1111/dme.12447
   PubMed Web of Science ®Google Scholar
• Liu S, Yuan Y, Xue Y, Xing C, Zhang B. Podocyte injury in diabetic kidney disease: a focus on mitochondrial dysfunction. Front Cell Dev Biol. 2022;10:832887. doi:10.3389/fcell.2022.832887
   PubMed Web of Science ®Google Scholar
• Yoshimura Y, Nishinakamura R. Podocyte development, disease, and stem cell research. Kidney Int. 2019;96(5):1077–1082. doi:10.1016/j.kint.2019.04.044
   PubMed Web of Science ®Google Scholar
• Altintas MM, Moriwaki K, Wei C, et al. Reduction of proteinuria through podocyte alkalinization. J Biol Chem. 2014;289(25):17454–17467. doi:10.1074/jbc.M114.568998
   PubMed Web of Science ®Google Scholar
• Chen Q, Kirk K, Shurubor YI, et al. Rewiring of glutamine metabolism is a bioenergetic adaptation of human cells with mitochondrial DNA mutations. Cell Metab. 2018;27(5):1007–1025.e5. doi:10.1016/j.cmet.2018.03.002
   PubMed Web of Science ®Google Scholar
• van Kuilenburg ABP, Tarailo-Graovac M, Richmond PA, et al. Glutaminase deficiency caused by short tandem repeat expansion in GLS. N Engl J Med. 2019;380(15):1433–1441. doi:10.1056/NEJMoa1806627
   PubMed Web of Science ®Google Scholar
• Alba-Loureiro TC, Ribeiro RF, Zorn TM, Lagranha CJ. Effects of glutamine supplementation on kidney of diabetic rat. Amino Acids. 2010;38(4):1021–1030. doi:10.1007/s00726-009-0310-3
   PubMed Web of Science ®Google Scholar
• Cao Y, Chen X, Zhu Z, et al. STING contributes to lipopolysaccharide-induced tubular cell inflammation and pyroptosis by activating endoplasmic reticulum stress in acute kidney injury. Cell Death Dis. 2024;15(3):217. doi:10.1038/s41419-024-06600-1
   PubMed Web of Science ®Google Scholar
• Huang W, Wang BO, Hou YF, et al. JAML promotes acute kidney injury mainly through a macrophage-dependent mechanism. JCI Insight. 2022;7(14). doi:10.1172/jci.insight.158571
   Web of Science ®Google Scholar
• Zhao L, Hao Y, Tang S, Han X, Li R, Zhou X. Energy metabolic reprogramming regulates programmed cell death of renal tubular epithelial cells and might serve as a new therapeutic target for acute kidney injury. Front Cell Dev Biol. 2023;11:1276217. doi:10.3389/fcell.2023.1276217
   PubMed Web of Science ®Google Scholar
• Weiss R, Meersch M, Gerke M, et al. Effect of glutamine administration after cardiac surgery on kidney damage in patients at high risk for acute kidney injury: a randomized controlled trial. Anesth Analg. 2023;137(5):1029–1038. doi:10.1213/ane.0000000000006288
   PubMed Web of Science ®Google Scholar
• Peng ZY, Zhou F, Wang HZ, et al. The anti-oxidant effects are not the main mechanism for glutamine’s protective effects on acute kidney injury in mice. Eur J Pharmacol. 2013;705(1–3):11–19. doi:10.1016/j.ejphar.2013.02.028
   PubMed Web of Science ®Google Scholar
• Hu YM, Pai MH, Yeh CL, Hou YC, Yeh SL. Glutamine administration ameliorates sepsis-induced kidney injury by downregulating the high-mobility group box protein-1-mediated pathway in mice. Am J Physiol Renal Physiol. 2012;302(1):F150–8. doi:10.1152/ajprenal.00246.2011
   PubMed Web of Science ®Google Scholar
• Kim YS, Jung MH, Choi MY, et al. Glutamine attenuates tubular cell apoptosis in acute kidney injury via inhibition of the c-Jun N-terminal kinase phosphorylation of 14-3-3. Crit Care Med. 2009;37(6):2033–2044. doi:10.1097/CCM.0b013e3181a005ba
   PubMed Web of Science ®Google Scholar
• Tsokos GC, Lo MS, Costa Reis P, Sullivan KE. New insights into the immunopathogenesis of systemic lupus erythematosus. Nat Rev Rheumatol. 2016;12(12):716–730. doi:10.1038/nrrheum.2016.186
   PubMed Web of Science ®Google Scholar
• Lee HT, Lin CS, Pan SC, et al. Alterations of oxygen consumption and extracellular acidification rates by glutamine in PBMCs of SLE patients. Mitochondrion. 2019;44:65–74. doi:10.1016/j.mito.2018.01.002
   PubMed Web of Science ®Google Scholar
• Shan J, Jin H, Xu Y. T cell metabolism: a new perspective on Th17/treg cell imbalance in systemic lupus erythematosus. Front Immunol. 2020;11:1027. doi:10.3389/fimmu.2020.01027
   PubMed Web of Science ®Google Scholar
• Zhang X, Wang G, Bi Y, Jiang Z, Wang X. Inhibition of glutaminolysis ameliorates lupus by regulating T and B cell subsets and downregulating the mTOR/P70S6K/4EBP1 and NLRP3/caspase-1/IL-1β pathways in MRL/lpr mice. Int Immunopharmacol. 2022;112:109133. doi:10.1016/j.intimp.2022.109133
   PubMed Web of Science ®Google Scholar
• Choi SC, Titov AA, Abboud G, et al. Inhibition of glucose metabolism selectively targets autoreactive follicular helper T cells. Nat Commun. 2018;9(1):4369. doi:10.1038/s41467-018-06686-0
   PubMedGoogle Scholar
• Perl A. Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases. Nat Rev Rheumatol. 2016;12(3):169–182. doi:10.1038/nrrheum.2015.172
   PubMed Web of Science ®Google Scholar
• Tsokos GC. Systemic lupus erythematosus in 2015: cellular and metabolic requirements of effector T cells. Nat Rev Rheumatol. 2016;12(2):74–76. doi:10.1038/nrrheum.2015.178
   PubMed Web of Science ®Google Scholar
• Warner LM, Adams LM, Sehgal SN. Rapamycin prolongs survival and arrests pathophysiologic changes in murine systemic lupus erythematosus. Arthritis Rheum. 1994;37(2):289–297. doi:10.1002/art.1780370219
   PubMedGoogle Scholar
• Lai ZW, Borsuk R, Shadakshari A, et al. Mechanistic target of rapamycin activation triggers IL-4 production and necrotic death of double-negative T cells in patients with systemic lupus erythematosus. J Immunol. 2013;191(5):2236–2246. doi:10.4049/jimmunol.1301005
   PubMed Web of Science ®Google Scholar
• Nakaya M, Xiao Y, Zhou X, et al. Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity. 2014;40(5):692–705. doi:10.1016/j.immuni.2014.04.007
   PubMed Web of Science ®Google Scholar
• Ross SJ, Critchlow SE. Emerging approaches to target tumor metabolism. Curr Opin Pharmacol. 2014;17:22–29. doi:10.1016/j.coph.2014.07.001
   PubMed Web of Science ®Google Scholar
• Rathmell JC. T cell Myc-tabolism. Immunity. 2011;35(6):845–846. doi:10.1016/j.immuni.2011.12.001
   PubMed Web of Science ®Google Scholar
• Lemberg KM, Vornov JJ, Rais R, Slusher BS. We’re Not ”DON” Yet: optimal Dosing and Prodrug Delivery of 6-Diazo-5-oxo-L-norleucine. Mol Cancer Ther. 2018;17(9):1824–1832. doi:10.1158/1535-7163.Mct-17-1148
   PubMed Web of Science ®Google Scholar
• Chittur SV, Klem TJ, Shafer CM, Davisson VJ. Mechanism for acivicin inactivation of triad glutamine amidotransferases. Biochemistry. 2001;40(4):876–887. doi:10.1021/bi0014047
   PubMed Web of Science ®Google Scholar
• Srikanth K, Debnath B, Jha T. Syntheses, biological evaluation and QSAR study on antitumor activity of 1,5-N,N’-disubstituted-2-(substituted benzenesulphonyl) glutamamides. Bioorg Med Chem. 2002;10(6):1841–1854. doi:10.1016/s0968-0896(02)00007-x
   PubMed Web of Science ®Google Scholar
• Rais R, Lemberg KM, Tenora L, et al. Discovery of DRP-104, a tumor-targeted metabolic inhibitor prodrug. Sci Adv. 2022;8(46):eabq5925. doi:10.1126/sciadv.abq5925
   PubMed Web of Science ®Google Scholar
• Rais R, Jančařík A, Tenora L, et al. Discovery of 6-Diazo-5-oxo-l-norleucine (DON) prodrugs with enhanced CSF delivery in monkeys: a potential treatment for glioblastoma. J Med Chem. 2016;59(18):8621–8633. doi:10.1021/acs.jmedchem.6b01069
   PubMed Web of Science ®Google Scholar
• Encarnación-Rosado J, Sohn ASW, Biancur DE, et al. Targeting pancreatic cancer metabolic dependencies through glutamine antagonism. Nat Cancer. 2024;5(1):85–99. doi:10.1038/s43018-023-00647-3
   PubMedGoogle Scholar
• Recouvreux MV, Grenier SF, Zhang Y, et al. Glutamine mimicry suppresses tumor progression through asparagine metabolism in pancreatic ductal adenocarcinoma. Nat Cancer. 2024;5(1):100–113. doi:10.1038/s43018-023-00649-1
   PubMedGoogle Scholar
• Thibault A, Samid D, Cooper MR, et al. Phase I study of phenylacetate administered twice daily to patients with cancer. Cancer. 1995;75(12):2932–2938. doi:10.1002/1097-0142(19950615)75:12<2932::AID-CNCR2820751221>3.0.CO;2-P
   PubMed Web of Science ®Google Scholar
• Bonnemaison ML, Marks-Nelson ES, Boesen EI. Sodium 4-phenylbutyrate treatment protects against renal injury in NZBWF1 mice. Clin Sci (Lond). 2019;133(2):167–180. doi:10.1042/cs20180562
   PubMed Web of Science ®Google Scholar
• Schulte ML, Fu A, Zhao P, et al. Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models. Nat Med. 2018;24(2):194–202. doi:10.1038/nm.4464
   PubMed Web of Science ®Google Scholar
• Hassanein M, Hoeksema MD, Shiota M, et al. SLC1A5 mediates glutamine transport required for lung cancer cell growth and survival. Clin Cancer Res. 2013;19(3):560–570. doi:10.1158/1078-0432.Ccr-12-2334
   PubMed Web of Science ®Google Scholar
• Silva C, Andrade N, Rodrigues I, Ferreira AC, Soares ML, Martel F. The pro-proliferative effect of interferon-γ in breast cancer cell lines is dependent on stimulation of ASCT2-mediated glutamine cellular uptake. Life Sci. 2021;286:120054. doi:10.1016/j.lfs.2021.120054
   PubMed Web of Science ®Google Scholar
• Wang W, Pan H, Ren F, Chen H, Ren P. Targeting ASCT2-mediated glutamine metabolism inhibits proliferation and promotes apoptosis of pancreatic cancer cells. Biosci Rep. 2022;42(3). doi:10.1042/bsr20212171
   Web of Science ®Google Scholar
• Marshall AD, van Geldermalsen M, Otte NJ, et al. ASCT2 regulates glutamine uptake and cell growth in endometrial carcinoma. Oncogenesis. 2017;6(7):e367. doi:10.1038/oncsis.2017.70
   PubMed Web of Science ®Google Scholar
• Li W, Ling Z, Wang J, et al. ASCT2-mediated glutamine uptake promotes Th1 differentiation via ROS-EGR1-PAC1 pathway in oral lichen planus. Biochem Pharmacol. 2023;216:115767. doi:10.1016/j.bcp.2023.115767
   PubMed Web of Science ®Google Scholar
• Lu J, Su Z, Li W, et al. ASCT2-mediated glutamine uptake of epithelial cells facilitates CCL5-induced T cell infiltration via ROS-STAT3 pathway in oral lichen planus. Int Immunopharmacol. 2023;119:110216. doi:10.1016/j.intimp.2023.110216
   PubMed Web of Science ®Google Scholar
• Kim JM, Im YN, Chung YJ, et al. Glutamine deficiency shifts the asthmatic state toward neutrophilic airway inflammation. Allergy. 2022;77(4):1180–1191. doi:10.1111/all.15121
   PubMed Web of Science ®Google Scholar
• Qin L, Cheng X, Wang S, et al. Discovery of novel aminobutanoic acid-based ASCT2 inhibitors for the treatment of non-small-cell lung cancer. J Med Chem. 2024;67(2):988–1007. doi:10.1021/acs.jmedchem.3c01093
   PubMed Web of Science ®Google Scholar
• Lyu XD, Liu Y, Wang J, et al. A novel ASCT2 Inhibitor, C118P, blocks glutamine transport and exhibits antitumour efficacy in breast cancer. Cancers (Basel). 2023;15(20). doi:10.3390/cancers15205082
   Web of Science ®Google Scholar
• Wang F, Li Z, Chen L, et al. Inhibition of ASCT2 induces hepatic stellate cell senescence with modified proinflammatory secretome through an IL-1α/NF-κB feedback pathway to inhibit liver fibrosis. Acta Pharm Sin B. 2022;12(9):3618–3638. doi:10.1016/j.apsb.2022.03.014
   PubMed Web of Science ®Google Scholar
• Shukla K, Ferraris DV, Thomas AG, et al. Design, synthesis, and pharmacological evaluation of bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide 3 (BPTES) analogs as glutaminase inhibitors. J Med Chem. 2012;55(23):10551–10563. doi:10.1021/jm301191p
   PubMed Web of Science ®Google Scholar
• Gross MI, Demo SD, Dennison JB, et al. Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol Cancer Ther. 2014;13(4):890–901. doi:10.1158/1535-7163.Mct-13-0870
   PubMed Web of Science ®Google Scholar
• Wang JB, Erickson JW, Fuji R, et al. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell. 2010;18(3):207–219. doi:10.1016/j.ccr.2010.08.009
   PubMed Web of Science ®Google Scholar
• Lukey MJ, Cluntun AA, Katt WP, et al. Liver-type glutaminase GLS2 is a druggable metabolic node in luminal-subtype breast cancer. Cell Rep. 2019;29(1):76–88.e7. doi:10.1016/j.celrep.2019.08.076
   PubMed Web of Science ®Google Scholar
• Sun Y, Feng X, Liu X, et al. Caudatan A, an undescribed human kidney-type glutaminase inhibitor with tetracyclic flavan from Ohwia caudata. Phytochemistry. 2018;152:22–28. doi:10.1016/j.phytochem.2018.04.013
   PubMed Web of Science ®Google Scholar
• Udupa S, Nguyen S, Hoang G, et al. Upregulation of the glutaminase II pathway contributes to glutamate production upon glutaminase 1 inhibition in pancreatic cancer. Proteomics. 2019;19(21–22):e1800451. doi:10.1002/pmic.201800451
   PubMed Web of Science ®Google Scholar
• Suzuki S, Venkatesh D, Kanda H, et al. GLS2 is a tumor suppressor and a regulator of ferroptosis in hepatocellular carcinoma. Cancer Res. 2022;82(18):3209–3222. doi:10.1158/0008-5472.Can-21-3914
   PubMed Web of Science ®Google Scholar
• Li C, Li M, Chen P, et al. Green tea polyphenols control dysregulated glutamate dehydrogenase in transgenic mice by hijacking the ADP activation site. J Biol Chem. 2011;286(39):34164–34174. doi:10.1074/jbc.M111.268599
   PubMed Web of Science ®Google Scholar
• Smith TJ. Green Tea Polyphenols in drug discovery - A success or failure? Expert Opin Drug Discov. 2011;6(6):589–595. doi:10.1517/17460441.2011.570750
   PubMed Web of Science ®Google Scholar
• Jin L, Li D, Alesi GN, et al. Glutamate dehydrogenase 1 signals through antioxidant glutathione peroxidase 1 to regulate redox homeostasis and tumor growth. Cancer Cell. 2015;27(2):257–270. doi:10.1016/j.ccell.2014.12.006
   PubMed Web of Science ®Google Scholar
• Jin Y, Li D, Lu S, et al. Ebselen reversibly inhibits human glutamate dehydrogenase at the catalytic site. Assay Drug Dev Technol. 2018;16(2):115–122. doi:10.1089/adt.2017.822
   PubMed Web of Science ®Google Scholar
• Hou W, Lu S, Zhao H, et al. Propylselen inhibits cancer cell growth by targeting glutamate dehydrogenase at the NADP(+) binding site. Biochem Biophys Res Commun. 2019;509(1):262–267. doi:10.1016/j.bbrc.2018.12.117
   PubMed Web of Science ®Google Scholar
• Chang SN, Keretsu S, Kang SC. Evaluation of decursin and its isomer decursinol angelate as potential inhibitors of human glutamate dehydrogenase activity through in silico and enzymatic assay screening. Comput Biol Med. 2022;151(Pt B):106287. doi:10.1016/j.compbiomed.2022.106287
   PubMedGoogle Scholar
• Bian Y, Hou W, Chen X, Fang J, Xu N, Ruan BH. Glutamate dehydrogenase as a promising target for hyperinsulinism hyperammonemia syndrome therapy. Curr Med Chem. 2022;29(15):2652–2672. doi:10.2174/0929867328666210825105342
   PubMed Web of Science ®Google Scholar
• Schulte ML, Dawson ES, Saleh SA, Cuthbertson ML, Manning HC. 2-Substituted Nγ-glutamylanilides as novel probes of ASCT2 with improved potency. Bioorg Med Chem Lett. 2015;25(1):113–116. doi:10.1016/j.bmcl.2014.10.098
   PubMed Web of Science ®Google Scholar