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Bulk RASFs were subjected to siRNA\u2010mediated knockdown (KD) of GLI3 or GLI1, followed by RNA sequencing. The effects of GANT61 on RASF proliferation, cell\u2010cycle progression, migration, viability, and apoptosis were assessed using EdU\/PI analysis, scratch assays, CCK\u20108 assays, and Annexin V\/PI flow cytometry.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      GLI3 expression was enriched in THY1\n                      <jats:sup>+<\/jats:sup>\n                      CD34\n                      <jats:sup>\u2212<\/jats:sup>\n                      RASFs at both mRNA and protein levels. GLI3 KD increased GLI1 expression and upregulated genes involved in inflammation, matrix remodeling, and cell cycle regulation, including IL6, IL11, IL24, IL33, MMP3, PLAU, CCNA2, and E2F1. Pathway enrichment analysis revealed activation of ECM\u2013receptor interaction, PI3K\u2013Akt, and TNF signaling. Co\u2010silencing GLI1 with GLI3 blunted the induction of IL11, IL24, IL33, CCNA2, E2F1, and PLAU observed with GLI3 KD alone, indicating that GLI1 mediates a subset of the transcriptional effects induced by GLI3 loss. GANT61 suppressed CCNA2 and E2F1 expression, inhibited RASF proliferation and migration, and did not markedly increase apoptosis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>GLI3 functions as a negative regulator of GLI1 and its downstream targets that drive the pathogenic behavior of RASFs. Targeting the GLI1\u2013GLI3 axis may represent a promising therapeutic strategy to modulate fibroblast\u2010driven inflammation and joint destruction in RA.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/1756-185x.70690","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T09:22:09Z","timestamp":1780651329000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Reciprocal Regulation of\n                    <scp>GLI1<\/scp>\n                    and\n                    <scp>GLI3<\/scp>\n                    Fine Tunes the Pathogenic Behavior of Synovial Fibroblasts in Rheumatoid Arthritis"],"prefix":"10.1111","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-2475-0437","authenticated-orcid":false,"given":"Motohiko","family":"Sato","sequence":"first","affiliation":[{"name":"Department of Rheumatology, Graduate School of Medical and Dental Sciences Institute of Science Tokyo (IST)  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7241-6662","authenticated-orcid":false,"given":"Tetsuya","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Graduate School of Medical and Dental Sciences Institute of Science Tokyo (IST)  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoji","family":"Komiya","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Graduate School of Medical and Dental Sciences Institute of Science Tokyo (IST)  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0268-8446","authenticated-orcid":false,"given":"Seiji","family":"Noda","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Graduate School of Medical and Dental Sciences Institute of Science Tokyo (IST)  Tokyo 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