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Due to the complex pathogenesis of RA and the limitations of current therapies, increasing research attention has been directed towards novel strategies targeting fibroblast-like synoviocytes (FLS), which are key cellular components of the hyperplastic pannus. Recent studies have highlighted the pivotal role of FLS in the initiation and progression of RA, driven by their tumour-like transformation and the secretion of pro-inflammatory mediators, including cytokines, chemokines and matrix metalloproteinases. The aggressive phenotype of RA-FLS is marked by excessive proliferation, resistance to apoptosis, and enhanced migratory and invasive capacities. Consequently, FLS-targeted therapies represent a promising avenue for the development of next-generation RA treatments. The efficacy of such strategies \u2013 particularly those aimed at modulating FLS signalling pathways \u2013 has been demonstrated in both preclinical and clinical settings, underscoring their therapeutic potential. This review provides an updated overview of the pathogenic mechanisms and functional roles of FLS in RA, with a focus on critical signalling pathways under investigation, including Janus kinase\/signal transducer and activator of transcription (JAK\/STAT), mitogen-activated protein kinase (MAPK), nuclear factor kappa B (NF-\u03baB), Notch and interleukin-1 receptor-associated kinase 4 (IRAK4). In addition, we discuss the emerging understanding of FLS-subset-specific contributions to immunometabolism and explore how computational biology is shaping novel targeted therapeutic strategies. A deeper understanding of the molecular and functional heterogeneity of FLS may pave the way for more effective and precise therapeutic interventions in RA.<\/jats:p>","DOI":"10.1017\/erm.2025.11","type":"journal-article","created":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T03:25:56Z","timestamp":1749093956000},"update-policy":"https:\/\/doi.org\/10.1017\/policypage","source":"Crossref","is-referenced-by-count":37,"title":["Unveiling the Therapeutic Potential: Targeting Fibroblast-like Synoviocytes in Rheumatoid Arthritis"],"prefix":"10.1017","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-7465-5486","authenticated-orcid":false,"given":"Siran","family":"Yue","sequence":"first","affiliation":[{"name":"Southern University of Science and Technology"},{"id":[{"id":"https:\/\/ror.org\/0145fw131","id-type":"ROR","asserted-by":"publisher"}],"name":"Hong Kong Baptist 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