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Emerging evidence from the field of immunometabolism reveals that altering the balance between oxidative phosphorylation (OXPHOS) and aerobic glycolysis, along with enhancing fatty acid synthesis and dysregulated glutamine metabolism, critically shapes lymphocyte activation, differentiation, and pathogenicity. Here, we review the metabolic pathways that regulate T cells and B cells. We discuss how changes in glucose, lipid, and mitochondrial metabolism influence immune responses that lead to chronic inflammation and autoimmunity in MS, RA, and T1D. Interestingly, similar immunometabolic changes, such as increased glycolysis, mitochondrial dysfunction, and mTOR signaling, have been identified in another autoimmune disorder, systemic lupus erythematosus (SLE). Connecting metabolic dysregulation to immune tolerance failure, this review highlights immunometabolism as a key mechanism in autoimmunity. Immunometabolic pathways represent a new avenue for precision immunotherapy, although challenges persist in targeting cells specifically without systemic toxicity. Understanding these metabolic adaptations and epigenetic\u2013metabolic crosstalk will be essential for translating these insights into next-generation therapies.<\/jats:p>","DOI":"10.1038\/s41423-026-01460-5","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T02:02:52Z","timestamp":1787536972000},"page":"1171-1193","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolic switch: lymphocytes and the onset of T-cell-mediated autoimmunity"],"prefix":"10.1038","volume":"23","author":[{"given":"Andisheh","family":"Mosaffa Jahromi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatemeh","family":"Mirzaei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Mirzazadeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9142-501X","authenticated-orcid":false,"given":"Seppo","family":"Meri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4160-7103","authenticated-orcid":false,"given":"Dieter","family":"Kabelitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kurosh","family":"Kalantar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,24]]},"reference":[{"key":"1460_CR1","doi-asserted-by":"publisher","first-page":"7666","DOI":"10.3390\/ijms25147666","volume":"25","author":"F Yasmeen","year":"2024","unstructured":"Yasmeen F, Pirzada RH, Ahmad B, Choi B, Choi S. 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