Fibroblast-like synoviocytes (FLS) are key effector cells in rheumatoid arthritis (RA), playing a central role in inflammation and cartilage destruction. RA is a chronic autoimmune disease characterized by synovial inflammation, joint damage, and systemic effects. FLS produce cytokines, proteases, and other mediators that perpetuate inflammation and degrade the extracellular matrix. These cells develop an aggressive phenotype, increasing invasiveness and exacerbating joint damage. Recent advances in understanding FLS biology, including their regulation of innate immune responses and intracellular signaling, provide new insights into RA pathogenesis. Targeting FLS could complement current therapies without significantly affecting adaptive immunity. RA synovium transforms from a quiescent structure to a hyperplastic, invasive tissue rich in immune cells. The intimal lining expands, with increased cellularity and a shift toward FLS and macrophage-like cells. These cells produce pro-inflammatory cytokines, chemokines, and growth factors, creating a paracrine/autocrine network that sustains inflammation and cartilage destruction. Osteoclasts and FLS are the primary effectors of bone and cartilage destruction, respectively. FLS originate from the synovial lining and sublining, with their accumulation influenced by cell proliferation, survival, and death. The RA environment promotes FLS survival and inhibits apoptosis through mechanisms involving Bcl-2 family proteins, NF-κB, and p53. Somatic mutations in key genes, such as p53, contribute to the aggressive phenotype of FLS. Cultured FLS exhibit unique properties, including invasive behavior and the ability to invade cartilage in vivo. FLS express adhesion molecules like integrins and VCAM-1, which facilitate their interaction with cartilage and matrix components. These molecules also modulate intracellular signaling pathways, including MAPKs and NF-κB, which regulate MMP production and cartilage destruction. MMPs, cathepsins, and aggrecanases are key proteases involved in cartilage degradation, with their expression regulated by cytokines and growth factors. FLS also contribute to the survival of other immune cells, such as T and B cells, through cell-cell interactions and soluble factors. They secrete cytokines, chemokines, and growth factors that support immune cell survival and function. FLS are active participants in innate immunity, expressing Toll-like receptors (TLRs) that recognize pathogen-associated molecular patterns and trigger inflammatory responses. TLR activation in FLS leads to increased expression of adhesion molecules, cytokines, and MMPs, contributing to chronic inflammation and joint damage. Understanding the biology of FLS is crucial for developing targeted therapies for RA.Fibroblast-like synoviocytes (FLS) are key effector cells in rheumatoid arthritis (RA), playing a central role in inflammation and cartilage destruction. RA is a chronic autoimmune disease characterized by synovial inflammation, joint damage, and systemic effects. FLS produce cytokines, proteases, and other mediators that perpetuate inflammation and degrade the extracellular matrix. These cells develop an aggressive phenotype, increasing invasiveness and exacerbating joint damage. Recent advances in understanding FLS biology, including their regulation of innate immune responses and intracellular signaling, provide new insights into RA pathogenesis. Targeting FLS could complement current therapies without significantly affecting adaptive immunity. RA synovium transforms from a quiescent structure to a hyperplastic, invasive tissue rich in immune cells. The intimal lining expands, with increased cellularity and a shift toward FLS and macrophage-like cells. These cells produce pro-inflammatory cytokines, chemokines, and growth factors, creating a paracrine/autocrine network that sustains inflammation and cartilage destruction. Osteoclasts and FLS are the primary effectors of bone and cartilage destruction, respectively. FLS originate from the synovial lining and sublining, with their accumulation influenced by cell proliferation, survival, and death. The RA environment promotes FLS survival and inhibits apoptosis through mechanisms involving Bcl-2 family proteins, NF-κB, and p53. Somatic mutations in key genes, such as p53, contribute to the aggressive phenotype of FLS. Cultured FLS exhibit unique properties, including invasive behavior and the ability to invade cartilage in vivo. FLS express adhesion molecules like integrins and VCAM-1, which facilitate their interaction with cartilage and matrix components. These molecules also modulate intracellular signaling pathways, including MAPKs and NF-κB, which regulate MMP production and cartilage destruction. MMPs, cathepsins, and aggrecanases are key proteases involved in cartilage degradation, with their expression regulated by cytokines and growth factors. FLS also contribute to the survival of other immune cells, such as T and B cells, through cell-cell interactions and soluble factors. They secrete cytokines, chemokines, and growth factors that support immune cell survival and function. FLS are active participants in innate immunity, expressing Toll-like receptors (TLRs) that recognize pathogen-associated molecular patterns and trigger inflammatory responses. TLR activation in FLS leads to increased expression of adhesion molecules, cytokines, and MMPs, contributing to chronic inflammation and joint damage. Understanding the biology of FLS is crucial for developing targeted therapies for RA.