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While tumor necrosis factor-\u03b1 (TNF\u03b1) is known to activate FLS, the upstream regulators that connect inflammatory stimulation with sustained stromal pathogenicity remain poorly defined. The LIN28A\u2012let-7 microRNA axis regulates proliferation and invasiveness in diverse pathological contexts, but its role in RA FLS remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>LIN28A\u2013let-7b regulation and functional consequences were investigated in TNF\u03b1-stimulated MH7A synoviocytes and primary murine FLS. Pathway inhibitor experiments were performed using p38 and NF-\u03baB inhibitors, and pharmacologic modulation of the LIN28\u2013let-7 interaction was evaluated using the small-molecule inhibitor C1632. Expression of LIN28A and let-7b was also examined in synovial tissues from collagen-induced arthritis (CIA) mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>TNF\u03b1 stimulation induced reciprocal regulation of LIN28A and let-7b, with increased LIN28A expression and reduced let-7b levels in MH7A cells and CIA synovial tissues. LIN28A overexpression enhanced proliferation, migration, invasion, and inflammatory mediator production, and increased expression of the let-7 target HMGA2 and matrix-remodeling enzymes. These changes were accompanied by activation of MAPK and NF-\u03baB signaling pathways. Inhibition of p38 or NF-\u03baB attenuated LIN28A-associated inflammatory gene expression. Primary fibroblast-like synoviocytes isolated from Lin28a transgenic mice recapitulated these phenotypes. In addition, disruption of the LIN28\u2013let-7 interaction using C1632 partially restored let-7b expression and suppressed migration, invasion, inflammatory gene expression, and signaling activation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>LIN28A may act as an upstream regulator of synoviocyte pathogenicity in RA. Targeting the LIN28A\u2012let-7b axis may represent a therapeutic strategy to modulate stromal contributions to disease progression.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13075-026-03809-7","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T07:45:50Z","timestamp":1776066350000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["LIN28A\u2012let-7b axis drives the aggressive and proinflammatory phenotype of rheumatoid arthritis fibroblast-like synoviocytes"],"prefix":"10.1186","volume":"28","author":[{"given":"Hee Young","family":"Chae","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyungrim","family":"Yi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su-Geun","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Yeong","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyejin","family":"Hyung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si-Yong","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanil","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang-Il","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong Kyu","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myoung Ok","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zae Young","family":"Ryoo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiwon","family":"Ko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soyeon","family":"Jang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,13]]},"reference":[{"issue":"23","key":"3809_CR1","doi-asserted-by":"publisher","first-page":"2205","DOI":"10.1056\/NEJMra1004965","volume":"365","author":"IB McInnes","year":"2011","unstructured":"McInnes IB, Schett G. 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