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

Authors

Haihui Han, Ya Ju, Zhiyu Chen, Zhuoyi Hu, Wenlei Qin, Yanhao Ge, Lamei Zhou, Yuanyuan Ding, Lijun Lu, Lu Jia, Wulin You, Yafeng Zhang, Xiaohui Meng

Published in

Journal of ethnopharmacology. Pages 122482. Oct 08, 2026. Epub Oct 08, 2026.

Abstract

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.
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.
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.
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.
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.

PMID:
42849824
Bibliographic data and abstract were imported from PubMed on 09 Oct 2026.

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