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Metrnl, a novel secreted protein linked to inflammatory immune regulation, has been implicated in RA pathogenesis, but its precise mechanisms remain undefined. This study aimed to elucidate Metrnl\u2019s role in RA progression and therapeutic potential. Proteomic analysis was employed to assess Metrnl\u2019s direct effects on RA fibroblast-like synoviocytes (RA-FLS). In vitro, LPS-induced RA-FLS were treated with Metrnl to evaluate proliferation, apoptosis, cell cycle progression, and expression of inflammatory cytokines (IL-6, IL-17, TNF-\u03b1) and angiogenic factors (PDGF, VEGF) via PPAR\u03b3 signaling. Collagen-induced arthritis (CIA) mice models were established to validate therapeutic efficacy, with Micro-CT and histology quantifying joint damage and inflammation. Proteomics results indicated Metrnl\u2019s multidirectional role in coordinating vascular homeostasis and immune-inflammatory network activation. Molecular biological results showed that Metrnl suppressed proliferation, promoted apoptosis, and downregulated IL-6, IL-17, TNF-\u03b1, PDGF, and VEGF through PPAR\u03b3 in LPS-induced RA-FLS cells. In CIA mice, Metrnl mitigated weight loss, reduced swollen joints, and improved behavioral scores. Micro-CT confirmed attenuated cartilage\/bone destruction and joint deformities, while histology revealed diminished inflammatory infiltration. Metrnl exerts anti-inflammatory and anti-angiogenic effects in RA by modulating PPAR\u03b3 signaling, highlighting its dual role in suppressing synovitis and vascular remodeling. These findings propose Metrnl as a novel therapeutic target to impede RA progression, offering insights into its pathological mechanisms. Furthermore, Metrnl mitigates bone erosion and joint deformities, underscoring its broader translational potential for treating bone-related disorders.<\/jats:p>","DOI":"10.1007\/s10753-025-02426-x","type":"journal-article","created":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T11:48:58Z","timestamp":1767700138000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Metrnl\/Meteorin-like\/IL-41 Alleviates Rheumatoid Arthritis Via PPAR\u03b3-Mediated Suppression of Inflammation, Angiogenesis, and Bone Destruction"],"prefix":"10.1007","volume":"49","author":[{"given":"Tao","family":"Sun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liping","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxuan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuoqi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,6]]},"reference":[{"key":"2426_CR1","doi-asserted-by":"publisher","first-page":"113953","DOI":"10.1016\/j.jep.2021.113953","volume":"272","author":"XJ Huang","year":"2021","unstructured":"Huang, X. J., J. Wang, A. Muhammad, H. Y. Tong, D. G. Wang, and J. Li et al. 2021. Systems pharmacology-based dissection of mechanisms of Tibetan medicinal compound Ruteng as an effective treatment for collagen-induced arthritis rats. Journal of Ethnopharmacology 272:113953.","journal-title":"Journal of Ethnopharmacology"},{"key":"2426_CR2","doi-asserted-by":"publisher","first-page":"1013660","DOI":"10.3389\/fmed.2022.1013660","volume":"9","author":"MEM El Shikh","year":"2022","unstructured":"El Shikh, M. E. M., R. El Sayed, N. A. R. Aly, E. Prediletto, R. Hands, and L. Fossati-Jimack et al. 2022. Follicular dendritic cell differentiation is associated with distinct synovial pathotype signatures in rheumatoid arthritis. Front Med (Lausanne) 9:1013660.","journal-title":"Front Med (Lausanne)"},{"issue":"6","key":"2426_CR3","doi-asserted-by":"publisher","first-page":"1986","DOI":"10.1007\/s10528-022-10202-x","volume":"60","author":"SA Fattah","year":"2022","unstructured":"Fattah, S. A., M. A. A. 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Li, J. Song, J. M. Liu, and C. Y. Miao. 2016. Metrnl: A secreted protein with new emerging functions. Acta Pharmacologica Sinica 37(5):571\u2013579.","journal-title":"Acta Pharmacologica Sinica"},{"issue":"2","key":"2426_CR6","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.clim.2014.11.006","volume":"156","author":"I Ushach","year":"2015","unstructured":"Ushach, I., A. M. Burkhardt, C. Martinez, P. A. Hevezi, P. A. Gerber, and B. A. Buhren et al. 2015. METEORIN-LIKE is a cytokine associated with barrier tissues and alternatively activated macrophages. Clin Immunol 156(2):119\u2013127.","journal-title":"Clin Immunol"},{"key":"2426_CR7","doi-asserted-by":"publisher","first-page":"108730","DOI":"10.1016\/j.pharmthera.2024.108730","volume":"263","author":"ZW Miao","year":"2024","unstructured":"Miao, Z. W., J. Chen, C. X. Chen, S. L. Zheng, H. Y. Zhao, and C. Y. Miao. 2024. Metrnl as a secreted protein: Discovery and cardiovascular research. 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