{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T15:54:40Z","timestamp":1792079680861,"version":"4.4.0"},"reference-count":80,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Rheumatoid Arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation. Recent studies have revealed that immune metabolites, particularly succinate, play a critical role in its pathogenesis. In this review, we systematically analyze the molecular mechanisms underlying succinate accumulation and elucidate how succinate drives inflammatory and immune dysregulation in RA. Hypoxia and inflammation microenvironment drive metabolic alterations, leading to succinate accumulation via three primary mechanisms: 1) succinate retention caused by impaired mitochondrial oxidation, 2) enhanced succinate synthesis through alternative biosynthetic pathways, and 3) increased succinate export into the extracellular space. Accumulated succinate exerts its pathogenic effects through three distinct pathways: (i) binding to its receptor Succinate Receptor 1 (SUCNR1) as an extracellular signaling molecule; (ii) stabilizing Hypoxia-Inducible Factor-1\u03b1 (HIF-1\u03b1) in the intracellular space; and (iii) acting as a key epigenetic modulator. These insights into succinate-mediated pathogenesis provide a rationale for the development of targeted RA therapies, including strategies aimed at SUCNR1, Succinate Dehydrogenase (SDH), and the combination of these metabolic interventions with existing anti-inflammatory treatments.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1842560","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T06:06:15Z","timestamp":1784095575000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Succinate-mediated metabolic alterations and signaling in RA: mechanisms and therapeutic implications"],"prefix":"10.3389","volume":"17","author":[{"given":"Yi","family":"Fan","sequence":"first","affiliation":[{"name":"Department of Rheumatology and Immunology, Beijing Key Laboratory of Non-invasive Diagnosis and Immunotherapy of Rheumatic Diseases, Peking University People\u2019s Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naidi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Beijing Key Laboratory of Non-invasive Diagnosis and Immunotherapy of Rheumatic Diseases, Peking University People\u2019s Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenxu","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoqi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Beijing Key Laboratory of Non-invasive Diagnosis and Immunotherapy of Rheumatic Diseases, Peking University People\u2019s 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