Fibroblast activation protein-α drives rheumatoid arthritis inflammation through the AKT/mTOR signaling pathway and its therapeutic effect by Wangbi granules

BACKGROUND: Fibroblast activation protein-α (FAPα), a transmembrane protein highly expressed in rheumatoid arthritis (RA) synovium, is postulated to drive inflammatory cascades, yet its mechanistic role remains elusive. Wangbi granules (WBG), a clinically used traditional Chinese medicine (TCM), show anti-RA potential but lack defined pharmacological evidence. PURPOSE: To identify FAPα as an inflammatory driver in RA pathogenesis and decipher how WBG suppresses FAPα-mediated AKT/mTOR signaling to resolve inflammation. METHODS: Employing synovial tissues from patients with RA and osteoarthritis (OA), collagen-induced arthritis (CIA) model rats, and lipopolysaccharide (LPS)-stimulated fibroblast-like synoviocytes (FLS). The pathological regulatory relationships among FAPα, the AKT/mTOR signaling pathway, and the inflammatory response were determined. Pharmacological, pharmacodynamic, and pharmacological experiments of WBG in the treatment of RA were conducted to explore whether WBG plays an anti-inflammatory role in RA by suppressing the expression of FAPα, thereby modulating the phosphorylation degree of the AKT/mTOR pathway. RESULTS: FAPα is highly expressed in RA patients and shows a positive correlation with inflammatory responses. In FLS, the high expression of FAPα can drive the activation of inflammatory responses by enhancing the phosphorylation of the AKT/mTOR signaling pathway. WBG can effectively alleviate arthritis symptoms in CIA rats. Network pharmacological analysis and transcriptome sequencing suggest that the mechanism of action may be closely related to the AKT/mTOR signaling pathway and inflammatory responses. Overexpression of the FAPα gene in FLS confirmed that WBG indeed regulates the phosphorylation level of the AKT/mTOR pathway by inhibiting the expression of FAPα, thereby exerting an anti-inflammatory effect on RA. CONCLUSIONS: This study uncovers FAPα as a novel driver of RA inflammation via AKT/mTOR activation and demonstrates WBG's therapeutic efficacy through FAPα inhibition, providing mechanistic insights and a potential TCM-based strategy for RA treatment.