{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T13:35:21Z","timestamp":1788442521963,"version":"build-2803163510"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T00:00:00Z","timestamp":1772150400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Methylglyoxal (MG), a toxic metabolic byproduct, functions as a potent antibacterial weapon deployed by macrophages. The glyoxalase system represents the primary microbial defense against MG, yet its role in\n                      <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                      pathogenesis remains incompletely defined.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      To define the function of the putative\n                      <jats:italic>M. tuberculosis glyoxalase<\/jats:italic>\n                      Rv0801 and its homolog MSMEG_5827, we used genetic engineering in\n                      <jats:italic>Mycobacterium smegmatis<\/jats:italic>\n                      MC\n                      <jats:sub>2<\/jats:sub>\n                      -155, coupled with growth and macrophage infection assays. Host mechanisms were dissected via transcriptomic and biochemical analysis of the KEAP1-NRF2 antioxidant pathway and pro-inflammatory responses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We demonstrate that Rv0801, conferring robust MG tolerance in a mycothiol (MSH)-dependent manner, is essential for bacterial fitness under MG stress. Mechanistically, Rv0801 orchestrates a dual-pathway interference within infected macrophages: by detoxifying MG, it suppresses the host KEAP1-NRF2 antioxidant pathway and concurrently dampens immunoprotective responses. This coordinated suppression compromises macrophage-mediated bacterial clearance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings establish Rv0801-mediated MG stress management as a critical virulence mechanism and highlight the bacterial glyoxalase as a promising target for tuberculosis therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1745502","type":"journal-article","created":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T06:50:24Z","timestamp":1772175024000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["A putative Mycobacterium tuberculosis glyoxalase Rv0801 promotes bacterial fitness by alleviating methylglyoxal stress and blunts NRF2-mediated antioxidant defenses"],"prefix":"10.3389","volume":"17","author":[{"given":"Haiqi","family":"Chen","sequence":"first","affiliation":[{"name":"Institute of Modern Biopharmaceuticals, School of Life Sciences, Southwest University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi\u2019ao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Modern Biopharmaceuticals, School of Life Sciences, Southwest University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Bio\u2010resources and Eco\u2010environment of the Ministry of Education, College of Life Sciences, Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyi","family":"He","sequence":"additional","affiliation":[{"name":"Institute of Modern Biopharmaceuticals, School of Life Sciences, Southwest University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abulimiti","family":"Abudukadier","sequence":"additional","affiliation":[{"name":"Institute of Modern Biopharmaceuticals, School of Life Sciences, Southwest University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Gynecology & Pediatrics Tuberculosis, Xi'an Chest Hospital","place":["Xi'an, Shaanxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qun","family":"Sun","sequence":"additional","affiliation":[{"name":"Key Laboratory of Bio\u2010resources and Eco\u2010environment of the Ministry of Education, College of Life Sciences, Sichuan University","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peibo","family":"Li","sequence":"additional","affiliation":[{"name":"Department of the Tuberculosis, Chongqing Public Health Medical Center","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianping","family":"Xie","sequence":"additional","affiliation":[{"name":"Institute of Modern Biopharmaceuticals, School of Life Sciences, Southwest University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,27]]},"reference":[{"key":"B1","doi-asserted-by":"crossref","DOI":"10.1042\/bj3440109","article-title":"Formation of glyoxal, methylglyoxal and 3-deoxyglucosone in the glycation of proteins by glucose","author":"Thornalley","year":"1999","journal-title":"Biochem J"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1080\/15376516.2020.1838019","article-title":"Methylglyoxal disturbs DNA repair and glyoxalase I system in Saccharomyces cerevisiae","volume":"31","author":"Pavin","year":"2021","journal-title":"Toxicol Mech Methods"},{"key":"B3","doi-asserted-by":"publisher","first-page":"101406","DOI":"10.1016\/j.molmet.2021.101406","article-title":"The activity of glyoxylase 1 is regulated by glucose-responsive phosphorylation on Tyr136","volume":"55","author":"Cortizo","year":"2022","journal-title":"Mol Metab"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1002\/iub.1324","article-title":"Cells producing their own nemesis: understanding methylglyoxal metabolism","volume":"66","author":"Chakraborty","year":"2014","journal-title":"IUBMB Life"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2023.1235581","article-title":"Association between GLO1 variants and gestational diabetes mellitus susceptibility in a Chinese population: a preliminary study","volume":"14","author":"Zeng","year":"2023","journal-title":"Front Endocrinol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1101\/2023.08.24.554661","article-title":"Disruption of Aldehyde Dehydrogenase 2 protects against bacterial infection","author":"Berry","year":"2023","journal-title":"bioRxiv"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.1016\/j.chom.2025.05.026","article-title":"Methylglyoxal is an antibacterial effector produced by macrophages during infection","volume":"33","author":"Anaya-Sanchez","year":"2025","journal-title":"Cell Host Microbe"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1501612","article-title":"Cutting edge: mycobacterium tuberculosis induces aerobic glycolysis in human alveolar macrophages that is required for control of intracellular bacillary replication","volume":"196","author":"Gleeson","year":"2016","journal-title":"J Immunol (Baltimore Md: 1950)"},{"key":"B9","doi-asserted-by":"publisher","first-page":"166425","DOI":"10.1016\/j.bbadis.2022.166425","article-title":"Immunometabolism and the modulation of immune responses and host defense: A role for methylglyoxal","volume":"1868","author":"Zhang","year":"2022","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"B10","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1007\/s11033-025-11389-z","article-title":"Molecular pathways of oxidative stress in diabetes: redox imbalance and insulin pathway dysregulation","volume":"53","author":"Wani","year":"2025","journal-title":"Mol Biol Rep"},{"key":"B11","doi-asserted-by":"publisher","first-page":"157729","DOI":"10.1016\/j.phymed.2025.157729","article-title":"Pharmacological inhibition of PGK1 by genipin reduces inflammation and oxidative damage in osteoarthritis","volume":"150","author":"Li","year":"2025","journal-title":"Phytomed: Int J Phytother Phytopharmacol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.24.16.7130-7139.2004","article-title":"Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2","volume":"24","author":"Kobayashi","year":"2004","journal-title":"Mol Cell Biol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0622-0","article-title":"A metabolite-derived protein modification integrates glycolysis with KEAP1-NRF2 signalling","volume":"562","author":"Bollong","year":"2018","journal-title":"Nature"},{"key":"B14","doi-asserted-by":"publisher","first-page":"e70633","DOI":"10.1002\/jbt.70633","article-title":"NRF2 pathway activation as a molecular toxicology mechanism in oxidative stress and lipid metabolic disorders","volume":"39","author":"Arif Asghar","year":"2025","journal-title":"J Biochem Mol Toxicol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00402.2010","article-title":"Adaptive induction of NF-E2-related factor-2-driven antioxidant genes in endothelial cells in response to hyperglycemia","volume":"300","author":"Ungvari","year":"2011","journal-title":"Am J Physiol Heart Circulatory Physiol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00023.2017","article-title":"The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis","volume":"98","author":"Yamamoto","year":"2018","journal-title":"Physiol Rev"},{"key":"B17","doi-asserted-by":"publisher","first-page":"108686","DOI":"10.1016\/j.fsi.2023.108686","article-title":"The Keap1-Nrf2 signaling pathway regulates antioxidant defenses of Ctenopharyngodon idella induced by bacterial infection","volume":"137","author":"Li","year":"2023","journal-title":"Fish Shellfish Immunol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"e0095323","DOI":"10.1128\/jvi.00953-23","article-title":"The master antioxidant defense is activated during EBV latent infection","volume":"97","author":"Wang","year":"2023","journal-title":"J Virol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"102464","DOI":"10.1016\/j.coph.2024.102464","article-title":"Effects of protein glycation and protective mechanisms against glycative stress","volume":"76","author":"Najjar","year":"2024","journal-title":"Curr Opin Pharmacol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2011.02.004","article-title":"Bacterial glyoxalase enzymes","volume":"22","author":"Suttisansanee","year":"2011","journal-title":"Semin Cell Dev Biol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"e1009819","DOI":"10.1371\/journal.ppat.1009819","article-title":"Detoxification of methylglyoxal by the glyoxalase system is required for glutathione availability and virulence activation in Listeria monocytogenes","volume":"17","author":"Anaya-Sanchez","year":"2021","journal-title":"PloS Pathogens"},{"key":"B22","doi-asserted-by":"publisher","first-page":"2322241","DOI":"10.1080\/20002297.2024.2322241","article-title":"Genetic characterization of glyoxalase pathway in oral streptococci and its contribution to interbacterial competition","volume":"16","author":"Zeng","year":"2024","journal-title":"J Oral Microbiol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"e1011441","DOI":"10.1371\/journal.ppat.1011441","article-title":"The methylglyoxal pathway is a sink for glutathione in Salmonella experiencing oxidative stress","volume":"19","author":"Kant","year":"2023","journal-title":"PloS Pathogens"},{"key":"B24","doi-asserted-by":"publisher","first-page":"e0056424","DOI":"10.1128\/aem.00564-24","article-title":"sll1019 and slr1259 encoding glyoxalase II improve tolerance of Synechocystis sp. PCC 6803 to methylglyoxal- and ethanol- induced oxidative stress by glyoxalase pathway","volume":"90","author":"Ji","year":"2024","journal-title":"Appl Environ Microbiol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1101\/2024.07.30.605887","article-title":"Identification of Glyoxalase A in Group B Streptococcus and its contribution to methylglyoxal tolerance and virulence","volume":"93","author":"Akbari","year":"2024","journal-title":"bioRxiv"},{"key":"B26","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1007\/s00203-021-02652-5","article-title":"Inducible knockdown of Mycobacterium smegmatis MSMEG_2975 (glyoxalase II) affected bacterial growth, antibiotic susceptibility, biofilm, and transcriptome","volume":"204","author":"Haris","year":"2021","journal-title":"Arch Microbiol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.71.12.6871-6883.2003","article-title":"The Mycobacterium tuberculosis complex-restricted gene cfp32 encodes an expressed protein that is detectable in tuberculosis patients and is positively correlated with pulmonary interleukin-10","volume":"71","author":"Huard","year":"2003","journal-title":"Infect Immun"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1096\/fj.11-199588","article-title":"Mycobacterium tuberculosis Rv0577, a novel TLR2 agonist, induces maturation of dendritic cells and drives Th1 immune response","volume":"26","author":"Byun","year":"2012","journal-title":"FASEB J: Off Publ Fed Am Soc Exp Biol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"e70052","DOI":"10.1002\/imo2.70052","article-title":"Cross-continental transmission and host adaptation of Mycobacterium tuberculosis in China unveiled by population history reconstruction and adaptive evolution signal detection","volume":"2","author":"Wu","year":"2025","journal-title":"iMetaOmics"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-0716-1460-0_16","article-title":"CRISPR interference (CRISPRi) for targeted gene silencing in mycobacteria","volume":"2314","author":"Wong","year":"2021","journal-title":"Methods Mol Biol (Clifton NJ)"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.00947-17","article-title":"CRISPR-cas12a-assisted recombineering in bacteria","volume":"83","author":"Yan","year":"2017","journal-title":"Appl Environ Microbiol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"e0536722","DOI":"10.1128\/spectrum.05367-22","article-title":"Coevolution of furA-Regulated Hyper-Inflammation and Mycobacterial Resistance to Oxidative Killing through Adaptation to Hydrogen Peroxide","volume":"11","author":"Fan","year":"2023","journal-title":"Microbiol Spectrum"},{"key":"B33","doi-asserted-by":"publisher","first-page":"109388","DOI":"10.1016\/j.bioorg.2025.109388","article-title":"Clinically present mycobacterium tuberculosis RNA polymerase subunit RpoB K446 mutation confers broad-spectrum antibiotics resistance via pupylation","volume":"169","author":"Shen","year":"2025","journal-title":"Bioorg Chem"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods (San Diego Calif)"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2010.07426.x","article-title":"The critical role of S-lactoylglutathione formation during methylglyoxal detoxification in Escherichia coli","volume":"78","author":"Ozyamak","year":"2010","journal-title":"Mol Microbiol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1111\/mmi.12489","article-title":"Methylglyoxal resistance in Bacillus subtilis: contributions of bacillithiol-dependent and independent pathways","volume":"91","author":"Chandrangsu","year":"2014","journal-title":"Mol Microbiol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.12.056","article-title":"Ergothioneine maintains redox and bioenergetic homeostasis essential for drug susceptibility and virulence of mycobacterium tuberculosis","volume":"14","author":"Saini","year":"2016","journal-title":"Cell Rep"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2012.10.012","article-title":"Glutathione and infection","volume":"1830","author":"Morris","year":"2013","journal-title":"Biochim Biophys Acta"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3390\/antiox10010019","article-title":"Interplay among oxidative stress, methylglyoxal pathway and S-glutathionylation","volume":"10","author":"de Bari","year":"2020","journal-title":"Antioxid (Basel Switzerland)"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2019.06.005","article-title":"Acid Fasting: Modulation of Mycobacterium tuberculosis Metabolism at Acidic pH","volume":"27","author":"Baker","year":"2019","journal-title":"Trends Microbiol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1128\/jb.108.3.1338-1347.1971","article-title":"Properties and mode of action of a bactericidal compound (=methylglyoxal) produced by a mutant of Escherichia coli","volume":"108","author":"Krymkiewicz","year":"1971","journal-title":"J Bacteriol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1007\/s00216-007-1682-4","article-title":"The structural modification of DNA nucleosides by nonenzymatic glycation: an in vitro study based on the reactions of glyoxal and methylglyoxal with 2\u2019-deoxyguanosine","volume":"390","author":"Li","year":"2008","journal-title":"Analytical Bioanalytical Chem"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/29.16.3433","article-title":"Methylglyoxal, an endogenous aldehyde, crosslinks DNA polymerase and the substrate DNA","volume":"29","author":"Murata-Kamiya","year":"2001","journal-title":"Nucleic Acids Res"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1800255115","article-title":"Antibiotic killing through oxidized nucleotides","volume":"115","author":"Rasouly","year":"2018","journal-title":"Proc Natl Acad Sci United States America"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.37.9.2913-2919.1999","article-title":"Isolation of rifampin-resistant mutants of Listeria monocytogenes and their characterization by rpoB gene sequencing, temperature sensitivity for growth, and interaction with an epithelial cell line","volume":"37","author":"Morse","year":"1999","journal-title":"J Clin Microbiol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2019.05.009","article-title":"Metabolic reprogramming: an innate cellular defence mechanism against intracellular bacteria","volume":"60","author":"Escoll","year":"2019","journal-title":"Curr Opin Immunol"},{"key":"B47","doi-asserted-by":"publisher","first-page":"103741","DOI":"10.1016\/j.redox.2025.103741","article-title":"The inhibition of TXNRD1 by methylglyoxal impairs the intracellular control of Mycobacterium tuberculosis","volume":"85","author":"Li","year":"2025","journal-title":"Redox Biol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1128\/microbiolspec.tnmi7-0023-2016","article-title":"Diabetes and tuberculosis","volume":"4","author":"Restrepo","year":"2016","journal-title":"Microbiol Spectrum"},{"key":"B49","doi-asserted-by":"publisher","first-page":"e0108622","DOI":"10.1128\/mbio.01086-22","article-title":"High glucose and carbonyl stress impair HIF-1-regulated responses and the control of mycobacterium tuberculosis in macrophages","volume":"13","author":"Ter\u00e1n","year":"2022","journal-title":"mBio"},{"key":"B50","doi-asserted-by":"publisher","first-page":"e2504018","DOI":"10.4014\/jmb.2504.04018","article-title":"Mitigation of bifidobacterium longum Z1 on methylglyoxal-induced glycotoxicity in neuron-2A cells by enhancing detoxification pathways","volume":"35","author":"Hong","year":"2025","journal-title":"J Microbiol Biotechnol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1745502\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T06:50:24Z","timestamp":1772175024000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1745502\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,27]]},"references-count":50,"alternative-id":["10.3389\/fimmu.2026.1745502"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1745502","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,27]]},"article-number":"1745502"}}