Celastrol Targets FGFR1 to Attenuate Synovial Inflammation and Joint Destruction in Rheumatoid Arthritis.

ETHNOPHARMACOLOGICAL RELEVANCE Natural products from traditional medicinal plants are valuable sources for discovering bioactive molecules targeting disease-relevant pathways. Tripterygium wilfordii Hook. f. has been traditionally used in Chinese medicine for rheumatic and inflammatory disorders. In this study, celastrol, a pentacyclic triterpenoid originally isolated from T. wilfordii, was identified through target-oriented natural product screening as a candidate FGFR1-binding compound.

Aim

OF THE STUDY This study aimed to define the pathogenic role of fibroblast growth factor receptor 1 (FGFR1) in rheumatoid arthritis progression and to determine whether celastrol, identified by target-oriented natural product screening, attenuates synovial inflammation and joint destruction through FGFR1 signaling suppression.

Materials And Methods

Multi-omics analyses, AAV-mediated FGFR1 gain- and loss-of-function experiments in collagen-induced arthritis rats, and MH7A fibroblast-like synoviocyte (FLS) assays were used to investigate FGFR1 function. SCENIC and CUT&Tag analyses were performed to examine FGFR1-associated transcriptional regulation. High-throughput virtual screening of a natural product library, surface plasmon resonance, and LC-MS/MS were used to identify and validate celastrol as an FGFR1-binding compound, followed by in vitro and in vivo assessment of its effects on FGFR1-driven pathology.

Results

FGFR1 overexpression was associated with increased synovial inflammation, cartilage damage, and bone erosion in collagen-induced arthritis rats, whereas FGFR1 knockdown showed protective effects. Mechanistically, FGFR1 appeared to enhance STAT1-mediated TGFB1 transcription, thereby promoting extracellular matrix remodeling, collagen deposition, and FLS invasion. High-throughput virtual screening of 4,667 natural compounds, followed by surface plasmon resonance and LC-MS/MS validation, identified celastrol as a candidate FGFR1-binding compound. Celastrol attenuated FGFR1-STAT1-TGF-β1 signaling and reduced extracellular matrix-related protein expression, FLS invasion, synovial fibrosis, and joint destruction.

Conclusions

Celastrol attenuates rheumatoid arthritis progression, at least in part, by targeting FGFR1 and suppressing the FGFR1-STAT1-TGF-β1 axis; these mechanistic findings, primarily derived from the MH7A cell line, warrant further validation in primary RA-FLS.