{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T12:45:12Z","timestamp":1791809112711,"version":"4.3.4"},"reference-count":97,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T00:00:00Z","timestamp":1790985600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T00:00:00Z","timestamp":1790985600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Rheumatoid arthritis (RA) arises from interactions among immune, stromal, and osteoimmune compartments, supporting interest in agents with multilevel activity, such as celastrol. This narrative review critically integrates evidence on its chemical\u2013pharmacological basis, immunomodulatory mechanisms, cellular effects, and translational potential in RA. Preclinical data show inhibition of inflammatory programs in macrophages and neutrophils, modulation of T- and B-cell responses, suppression of pathogenic fibroblast-like synoviocyte (FLS) functions, and reduced osteoclastogenesis and structural damage. COMM domain-containing proteins 3 and 8 (COMMD3\/8) provide the strongest causal validation, while insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) has biophysical and functional support; numerous inflammatory and metabolic nodes primarily represent downstream signaling. Multicellular models support functional convergence, but intercellular causation in RA remains limited; directional functional evidence for dendritic cell\u2013T-cell modulation comes from non-rheumatoid models, and no persistent synovial reprogramming has been demonstrated. Low bioavailability, multitarget covalent pharmacology, a narrow therapeutic window, and contributions from delivery carriers constrain translational interpretation. Addressing these translational challenges explicitly can help guide future research to improve celastrol\u2019s safety and efficacy, which is essential for clinical application.<\/jats:p>","DOI":"10.3390\/ijms27198834","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T12:31:31Z","timestamp":1791203491000},"page":"8834","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Celastrol in Rheumatoid Arthritis: Immunomodulatory Mechanisms, Multicellular Convergence, and Translational Challenges"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7267-1482","authenticated-orcid":false,"given":"Fernanda-Isadora","family":"Corona-Meraz","sequence":"first","affiliation":[{"name":"Universidad de Guadalajara, Centro Universitario de Tonal\u00e1, Departamento de Ciencias Biom\u00e9dicas, Centro de Investigaci\u00f3n Multidisciplinario en Salud, Tonal\u00e1 C.P. 45425, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6756-4316","authenticated-orcid":false,"given":"Beatriz Teresita","family":"Mart\u00edn-M\u00e1rquez","sequence":"additional","affiliation":[{"name":"Universidad de Guadalajara, Centro Universitario de Ciencias de la Salud, Departamento de Biolog\u00eda Molecular y Gen\u00f3mica, Instituto de Investigaci\u00f3n en Reumatolog\u00eda y Sistema M\u00fasculo Esquel\u00e9tico, Guadalajara C.P. 44340, Jalisco, Mexico"},{"name":"Universidad de Guadalajara, Centro Universitario de Ciencias de la Salud, Departamento de Biolog\u00eda Molecular y Gen\u00f3mica, Cuerpo Acad\u00e9mico UDG-CA-703 \u201cInmunolog\u00eda y Reumatolog\u00eda\u201d, Guadalajara C.P. 44340, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9593-7562","authenticated-orcid":false,"given":"Luis E.","family":"Cobos-Puc","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias Qu\u00edmicas, Universidad Aut\u00f3noma de Coahuila, Boulevard V. 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