{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T19:48:05Z","timestamp":1793908085940,"version":"4.8.0"},"reference-count":130,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T00:00:00Z","timestamp":1776988800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by persistent synovitis, progressive joint destruction, and diverse extra-articular complications. Increasing evidence indicates that RA pathogenesis is not driven by isolated inflammatory events, but by a tightly interconnected network involving immune dysregulation, metabolic reprogramming, and aberrant mechanotransduction. This review synthesizes recent advances in these three pathogenic dimensions and proposes an integrated framework for understanding RA as a systemic, self-reinforcing disease process. We highlight how inflammatory circuits, particularly the IL-6\/STAT3 and TNF-\u03b1\/NF-\u03baB axes, interact with autoantibody- and neutrophil extracellular trap-mediated immune propagation beyond the synovium. We further discuss how glycolytic rewiring, succinate accumulation, and microbiota-derived metabolites amplify inflammatory signaling and tissue remodeling. In parallel, altered extracellular matrix stiffness and activation of the integrin-FAK-YAP\/TAZ pathway sustain pathogenic fibroblast behavior through mechano-epigenetic coupling. Collectively, these pathways form a feed-forward loop that links local synovial inflammation with systemic organ involvement. A systems-level understanding of these interactions may provide a stronger foundation for biomarker-guided stratification and the development of multi-target, mechanism-based therapeutic strategies in RA.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1825523","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T09:46:53Z","timestamp":1777024013000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Multifactorial pathogenesis of rheumatoid arthritis: interaction between inflammation, metabolic dysregulation, and tissue mechanics"],"prefix":"10.3389","volume":"17","author":[{"given":"Yundong","family":"Xu","sequence":"first","affiliation":[{"name":"First Clinical Medical College, Yunnan University of Chinese Medicine","place":["Kunming, Yunnan, China"]},{"name":"Joint Graduate School of Traditional Chinese Medicine of China","place":["Suzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Yang","sequence":"additional","affiliation":[{"name":"First Clinical Medical College, Yunnan University of Chinese Medicine","place":["Kunming, Yunnan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongting","family":"Lu","sequence":"additional","affiliation":[{"name":"First Clinical Medical College, Yunnan University of Chinese Medicine","place":["Kunming, Yunnan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Zhang","sequence":"additional","affiliation":[{"name":"First Clinical Medical College, Yunnan University of Chinese Medicine","place":["Kunming, Yunnan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Xu","sequence":"additional","affiliation":[{"name":"First Clinical Medical College, Yunnan University of Chinese Medicine","place":["Kunming, Yunnan, 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