This study examined the role of actin-bundling protein FSCN1 in fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA), using human synovial tissue (RA, OA, and healthy controls; n=6 each), FLS-specific knockout and overexpression mouse models, transcriptome profiling, RNA immunoprecipitation sequencing, and mass spectrometry to define its mechanism and therapeutic potential.
FSCN1 was significantly upregulated in RA synovium (P<0.001), predominantly in PDPN+ FLS. Mechanistically, FSCN1 sequestered TRIM38, blocking IGF2BP1 ubiquitination and sustaining PI3K-AKT/NF-κB signaling. FLS-specific FSCN1 knockout reduced knee swelling, pain behavior, synovial inflammation, and OARSI scores (P<0.0196); pharmacological inhibition with imipramine or NP-G2-044 suppressed FLS activation and alleviated arthritis pathology in mice (P<0.001).
- All in vivo efficacy data are from mouse arthritis models; direct human therapeutic validation is lacking. - Human synovial samples are small (n=6 per group), limiting generalizability. - Imipramine is an established antidepressant with known off-target effects, complicating interpretation of FSCN1-specific pharmacology.
FSCN1 is a mechanistically validated driver of FLS aggression in RA via the TRIM38–IGF2BP1–PI3K/NF-κB axis; while no clinical agents are yet approved for this target, FSCN1 inhibitors (including repurposed imipramine) show preclinical promise and may warrant early-phase evaluation in RA.
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