{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T18:50:48Z","timestamp":1791312648704,"version":"4.3.1"},"reference-count":54,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"958","funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI089714"],"award-info":[{"award-number":["R01AI089714"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01DK130884"],"award-info":[{"award-number":["R01DK130884"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["K01DK124358"],"award-info":[{"award-number":["K01DK124358"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R03DK139233"],"award-info":[{"award-number":["R03DK139233"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009576","name":"Kenneth\u00a0Rainin\u00a0Foundation","doi-asserted-by":"publisher","award":["20220024"],"award-info":[{"award-number":["20220024"]}],"id":[{"id":"10.13039\/100009576","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015724","name":"Center for Cell Signaling in Gastroenterology, Mayo Clinic","doi-asserted-by":"publisher","award":["P30DK084567"],"award-info":[{"award-number":["P30DK084567"]}],"id":[{"id":"10.13039\/100015724","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Signal."],"published-print":{"date-parts":[[2026,10,6]]},"abstract":"<jats:p>\n                    CD4\n                    <jats:sup>+<\/jats:sup>\n                    effector T helper 1 (T\n                    <jats:sub>H<\/jats:sub>\n                    1) cells drive inflammatory bowel disease (IBD). Here, we investigated how integrated signaling, metabolic, and epigenetic programs sustain their pathogenic persistence. We found that enforcing mitochondrial pyruvate metabolism with methyl pyruvate (MePyr) suppressed T\n                    <jats:sub>H<\/jats:sub>\n                    1 cell effector function and induced the acquisition of a regulatory-like phenotype. MePyr suppressed the activity of glycogen synthase kinase 3\u03b2 (GSK3\u03b2), promoting a metabolic shift from glycolysis toward oxidative phosphorylation (OXPHOS) and limiting the accumulation of intracellular acetyl-CoA. This metabolic reprogramming decreased histone H3 acetylation at genes encoding inflammatory cytokines, thereby decreasing T\n                    <jats:sub>H<\/jats:sub>\n                    1 cell\u2013associated gene expression. Restoration of inflammatory cytokine production by acetate supplementation or histone deacetylase inhibition established acetyl-CoA\u2013dependent histone acetylation as a mechanistic link between metabolic flux and effector function. Conversely, the cytokine interleukin-21 enhanced T\n                    <jats:sub>H<\/jats:sub>\n                    1 cell effector activity by promoting a GSK3\u03b2-dependent shift from OXPHOS to glycolysis. Single-cell transcriptomic analysis of Crohn\u2019s disease tissue revealed enrichment of glycolytic gene programs in nonregulatory CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells. Consistent with these findings, pharmacologic inhibition of GSK3\u03b2 attenuated disease severity in a T cell\u2013transfer mouse model of colitis. Together, these findings identify a GSK3\u03b2-dependent metabolic-epigenetic axis that sustains T\n                    <jats:sub>H<\/jats:sub>\n                    1 cell pathogenicity and highlight GSK3\u03b2 as a potential therapeutic target for IBD.\n                  <\/jats:p>","DOI":"10.1126\/scisignal.aeb2392","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T17:58:05Z","timestamp":1791309485000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Metabolic reprogramming of pathogenic CD4\n                    <sup>+<\/sup>\n                    T helper cells attenuates inflammatory bowel disease in mice"],"prefix":"10.1126","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7180-4952","authenticated-orcid":true,"given":"Shravan K.","family":"Mishra","sequence":"first","affiliation":[{"name":"Immunometabolism and Mucosal Immunity Laboratory, Mayo Clinic, Rochester, MN 55905, USA."},{"name":"Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9769-9605","authenticated-orcid":true,"given":"Leena M.","family":"Abdelrahman","sequence":"additional","affiliation":[{"name":"Immunometabolism and Mucosal Immunity Laboratory, Mayo Clinic, Rochester, MN 55905, USA."},{"name":"Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1104-4776","authenticated-orcid":true,"given":"Hyun Se Kim","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5145-303X","authenticated-orcid":true,"given":"Luc\u00eda","family":"Valenzuela-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9484-6209","authenticated-orcid":true,"given":"Dina F.","family":"Manna","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5124-4925","authenticated-orcid":true,"given":"Tanner J.","family":"Abram","sequence":"additional","affiliation":[{"name":"Immunometabolism and Mucosal Immunity Laboratory, Mayo Clinic, Rochester, MN 55905, USA."},{"name":"Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5662-5034","authenticated-orcid":true,"given":"Lama Mohamed","family":"Ali","sequence":"additional","affiliation":[{"name":"Immunometabolism and Mucosal Immunity Laboratory, Mayo Clinic, Rochester, MN 55905, USA."},{"name":"Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2750-9508","authenticated-orcid":true,"given":"Heidi M.","family":"Davidson","sequence":"additional","affiliation":[{"name":"Immunometabolism and Mucosal Immunity Laboratory, Mayo Clinic, Rochester, MN 55905, USA."},{"name":"Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9789-4697","authenticated-orcid":true,"given":"Omar M.","family":"Hassan","sequence":"additional","affiliation":[{"name":"Immunometabolism and Mucosal Immunity Laboratory, Mayo Clinic, Rochester, MN 55905, USA."},{"name":"Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"William A.","family":"Faubion","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0494-0924","authenticated-orcid":true,"given":"Petra","family":"Hirsova","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9547-2195","authenticated-orcid":true,"given":"Adebowale O.","family":"Bamidele","sequence":"additional","affiliation":[{"name":"Immunometabolism and Mucosal Immunity Laboratory, Mayo Clinic, Rochester, MN 55905, USA."},{"name":"Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA."},{"name":"Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2016.70"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2017.04.013"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.01.007"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8456300"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-016-0244-y"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1200439"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa4282"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.02.007"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20061099"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20061082"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2010.08.010"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.08.008"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.06.029"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2024.09.021"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.05.016"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.09.021"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri3874"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1515\/znb-1958-0806"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-019-0123-5"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf6284"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1311-3"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI76012"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.02.012"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2014.11.016"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-1925"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbabio.2008.11.009"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4296"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2024.01.026"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.3109\/10428194.2015.1122781"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2006.10.009"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2012.06.001"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1164097"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M004160200"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0442-x"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2004.12.042"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2008.01.041"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1301454"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-05-021600"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M110.000299"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-021-02205-y"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.1.202"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M803614200"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep34802"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2736(82)90354-6"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-2999(97)01507-0"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2014.05.008"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-022-00658-y"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2022.09.016"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-022-00572-w"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.03.016"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.adh8342"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-018-0084-8"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2024.102511"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2018.08.009"}],"container-title":["Science Signaling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scisignal.aeb2392","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T17:58:08Z","timestamp":1791309488000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scisignal.aeb2392"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,6]]},"references-count":54,"journal-issue":{"issue":"958","published-print":{"date-parts":[[2026,10,6]]}},"alternative-id":["10.1126\/scisignal.aeb2392"],"URL":"https:\/\/doi.org\/10.1126\/scisignal.aeb2392","relation":{},"ISSN":["1945-0877","1937-9145"],"issn-type":[{"value":"1945-0877","type":"print"},{"value":"1937-9145","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,6]]},"assertion":[{"value":"2025-08-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-15","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-06","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eaeb2392"}}