Yu-Xue-Bi capsule ameliorates aggressive synovitis and joint damage in rheumatoid arthritis via modulating the SUCNR1/HIF-1α/TRPV1 axis.

Background: Specific treatment for rheumatoid arthritis (RA) is still an unmet need. Yu-Xue-Bi (YXB) capsule effectively treats RA with blood stasis syndrome (BS). However, its mechanism remains unclear.

Purpose: Exploring and elucidating the therapeutic effect and pharmacological mechanism of YXB capsule in treating RA.

Methods: This study identified differentially expressed genes (DEGs) in patients with RA and BS compared to healthy controls using clinical transcriptomics data. Clinical symptoms of RA and BS, and the related genes were collected from the SoFDA and HPO databases. Candidate bioactive constituents in YXB were identified via UPLC-QTOF/MS and evaluated using ADMET rules. Putative targets were predicted, and a network linking disease-related DEGs and drug targets was constructed. Key targets were screened utilizing random walk-with-restart (RWR) algorithms and verified through experiments using rat models of collagen-induced arthritis with BS (CIA-BS model) in vivo.

Results: We found 1220 DEGs along with 976 clinical symptom-related genes, as RA with BS-related genes. Chemical profiling identified 193 YXB constituents, with 98 meeting optimal ADMET criteria. We predicted 459 putative targets for these constituents. Network calculations screened 209 key targets, 129 RA with BS-related genes and 92 YXB targets involved in immune inflammation, blood stagnation, and hyperalgesia imbalance. Notably, the SUCNR1/HIF-1α/TRPV1 axis was enriched by YXB targets against RA with BS. Experimentally, YXB inhibited inflamed joint deterioration, including synovial inflammation, cartilage damage and bone erosion, relieving mechanical and cold allodynia hyperglasia. It reversed hemorrheology and vascular function in CIA-BS rats, restoring SDHB and eNOS expression, preventing SDHA, SUCNR1 and HIF-1α activation, reducing SUCN, TNF-α and IL-1β production, and TRPV1 and TRPA1 expression.

Conclusion: Our data support YXB's therapeutic effects on aggressive RA-BS by modulating the SUCNR1/HIF-1α/TRPV1 axis.