<scp>FSCN1</scp> promotes rheumatoid arthritis progression via inhibiting <scp>TRIM38</scp> ‐mediated ubiquitination of <scp>IGF2BP1</scp>  in fibroblast‐like synoviocytes

OBJECTIVE: Fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) synovium acquire a unique aggressive phenotype and produce cytokines that perpetuate inflammation and proteases that contribute to cartilage destruction. Actin bundling protein Fascin-1 (FSCN1) is involved in FLS migration and invasion, but its role and mechanism in FLS phenotypic activation remain unclear. METHODS: FSCN1 expression was analyzed in the synovium from healthy controls (n=6), RA (n=6) and osteoarthritis (n=6) patients with written informed consent obtained prior to sample collection, as well as synovium from control (n=6) and arthritic mice (n=6). Transcriptome profiling, RNA immunoprecipitation sequencing and mass spectrometry analysis were performed to determine the underlying mechanism. FLS-specific FSCN1 knockout, FSCN1 intra-articular overexpression mice, and FSCN1 inhibitors were utilized to characterize the role and therapeutic potential of FSCN1 in experimental arthritis (n=5-8). RESULTS: FSCN1 was significantly increased in RA synovium and predominantly localized to PDPN-positive FLS (P<0.001). FSCN1 overexpression enhanced F-actin remodeling, FLS migration, invasion, proliferation, and inflammatory activation, and exacerbated synovitis and cartilage damage in arthritis mouse models (P<0.0026). Conversely, FLS-specific FSCN1 ablation reduced knee swelling, pain-related behavior, synovial inflammation, and OARSI scores in arthritis mouse models (P<0.0196). Mechanistically, FSCN1 promoted F-actin fiber formation, spatially sequestered TRIM38, inhibited TRIM38-mediated IGF2BP1 ubiquitination, and sustained PI3K-AKT/NF-κB signaling. The FSCN1 inhibitors imipramine and NP-G2-044 suppressed FLS activation and alleviated arthritis pathology in mice (P<0.001). DISCUSSION: Pharmacological inhibition of FSCN1 restrains synovial inflammation and joint destruction by suppressing the aggressive phenotype change of FLS, representing a promising therapeutic strategy against RA.