{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T12:47:12Z","timestamp":1793278032321,"version":"4.5.0"},"reference-count":36,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"862","funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82473931"],"award-info":[{"award-number":["82473931"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82430114"],"award-info":[{"award-number":["82430114"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82204405"],"award-info":[{"award-number":["82204405"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Natural Science Foundation of Anhui Provincial","award":["2408085MH217"],"award-info":[{"award-number":["2408085MH217"]}]},{"name":"Young Elite Scientists Sponsorship Program by Anhui Association for Science and Technology","award":["RCTJ202427"],"award-info":[{"award-number":["RCTJ202427"]}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2026,8,12]]},"abstract":"<jats:p>\n                    High succinate concentrations are implicated in rheumatoid arthritis (RA) and other inflammatory diseases through G protein\u2013coupled receptor 91 (GPR91)\u2013mediated signaling. Despite the therapeutic potential of targeting GPR91, conflicting reports on the receptor\u2019s inflammatory roles have hindered treatment development. Here, we report that the effects of succinate on GPR91 signaling are biphasic and concentration dependent. At physiological succinate concentration, membrane-localized GPR91 promotes M2 polarization through G\n                    <jats:sub>q<\/jats:sub>\n                    -mediated activation of phospholipase C and intracellular calcium mobilization. In RA, elevated succinate induces GPR91 internalization and mitochondrial translocation, thereby disrupting G\n                    <jats:sub>q<\/jats:sub>\n                    signaling. Mechanistically, mitochondrial GPR91 recruits G\n                    <jats:sub>s<\/jats:sub>\n                    proteins and, together with intracellular succinate, activates the cyclic adenosine monophosphate (cAMP)\u2013protein kinase A (PKA) pathway. PKA then phosphorylates cytidine\/uridine monophosphate kinase 2 at serine-404, stabilizing it to enhance mitochondrial DNA (mtDNA) synthesis. Newly synthesized mtDNA is oxidized (forming ox-mtDNA) and released into the cytosol, activating the cyclic GMP-AMP synthase\u2013stimulator of interferon genes pathway to drive macrophage inflammation. Myeloid-specific GPR91 deletion or inhibition of intracellular succinate accumulation alleviates arthritis in mice. This study reveals that GPR91 reprograms signaling by subcellular relocation, providing a promising therapeutic strategy for autoimmune diseases.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.aea8468","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T17:58:18Z","timestamp":1786557498000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":2,"title":["Succinate drives macrophage inflammation by promoting GPR91 mitochondrial signaling in rheumatoid arthritis"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-8087-0888","authenticated-orcid":true,"given":"Wankang","family":"Zhang","sequence":"first","affiliation":[{"name":"Institute of Clinical Pharmacology, School of Pharmacy; Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei 230032, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7107-846X","authenticated-orcid":true,"given":"Luping","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology, School of Pharmacy; Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei 230032, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9892-3732","authenticated-orcid":true,"given":"Yingjie","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0399-0537","authenticated-orcid":true,"given":"Yao","family":"Mu","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology, School of Pharmacy; Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei 230032, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8449-1971","authenticated-orcid":true,"given":"Lei","family":"Qiu","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology, School of Pharmacy; Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei 230032, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7656-6368","authenticated-orcid":true,"given":"Xinyu","family":"Feng","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology, School of Pharmacy; Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei 230032, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1440-5696","authenticated-orcid":true,"given":"Yueye","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology, School of Pharmacy; Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei 230032, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8939-2156","authenticated-orcid":true,"given":"Jiemin","family":"Zhao","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology, School of Pharmacy; Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei 230032, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6684-5960","authenticated-orcid":true,"given":"Yan","family":"Chang","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology, School of Pharmacy; Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei 230032, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3117-9598","authenticated-orcid":true,"given":"Wei","family":"Wei","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology, School of Pharmacy; Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei 230032, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6296-6973","authenticated-orcid":true,"given":"Xuezhi","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology, School of Pharmacy; Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei 230032, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)01525-8"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2023.09.013"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2665-9913(25)00028-1"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2015.246"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.40504"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2023.12.001"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.38021"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2015-208476"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/cei\/uxab021"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-018-0708-5"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.07.030"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature02488"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2007.03.016"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2016.01.008"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature11986"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20160061"},{"key":"e_1_3_2_18_2","doi-asserted-by":"crossref","unstructured":"T. Rubi\u0107-Schneider N. Carballido-Perrig C. Regairaz L. Raad S. Jost C. Rauld B. Christen G. Wieczorek R. Kreutzer J. Dawson G. Lametschwandner A. Littlewood-Evans J. M. Carballido GPR91 deficiency exacerbates allergic contact dermatitis while reducing arthritic disease in mice. Allergy 72 444\u2013452 (2017).","DOI":"10.1111\/all.13005"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201800285"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0372-7"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2020.11.004"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109246"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15621"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abm1638"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2024.103253"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2015.02.004"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.08.005"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2016.69"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2022.06.007"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/d41586-018-05764-z"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.106.132282"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1418716112"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI59097"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abi7495"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2016-210000"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2017.07.017"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-019-1767-y"}],"container-title":["Science Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.aea8468","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T17:58:41Z","timestamp":1786557521000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.aea8468"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,12]]},"references-count":36,"journal-issue":{"issue":"862","published-print":{"date-parts":[[2026,8,12]]}},"alternative-id":["10.1126\/scitranslmed.aea8468"],"URL":"https:\/\/doi.org\/10.1126\/scitranslmed.aea8468","relation":{},"ISSN":["1946-6234","1946-6242"],"issn-type":[{"value":"1946-6234","type":"print"},{"value":"1946-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,12]]},"assertion":[{"value":"2025-07-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-14","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-20","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eaea8468"}}