Network pharmacology-based exploration of the synergistic efficacy and detoxification mechanisms of Tripterygium wilfordii and Epimedium brevicornum in treating rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease with limited therapeutic options. The herbal compatibility of Tripterygium wilfordii Hook. f. (Leigongteng, LGT) and Epimedium brevicornum Maxim. (Yinyanghuo, YYH), widely used in Traditional Chinese Medicine, has shown promising efficacy in RA treatment, yet its synergistic mechanisms and hepatoprotective effects remain unclear. In this study, we systematically investigated the therapeutic and hepatotoxicity-attenuating mechanisms of LGT-YYH using integrated network pharmacology and molecular docking approaches. Bioactive compounds and corresponding targets from LGT and YYH were retrieved from the TCMSP database, while RA- and hepatotoxicity-related targets were collected from public databases and microarray datasets. Protein-protein interaction networks, hub protein targets identification, and functional enrichment analyses revealed that 65 LGT and 26 YYH bioactive compounds collectively interact with 527 RA-related targets, with hub targets including PTPN11, SRC, EGFR, MAPK1, and MAPK8 central to the therapeutic network. KEGG enrichment highlighted the MAPK signaling pathway as a key mechanism of anti-RA activity. Furthermore, 243 targets were associated with LGT-induced hepatotoxicity, and YYH components, particularly icariin, kaempferol, and epimedin B, exhibited binding to hepatotoxicity-related targets such as AKT1 and ESR1, suggesting a hepatoprotective role via the AKT1-ESR1-Nrf2 axis. These findings indicate that LGT-YYH exerts synergistic anti- RA effects by modulating MAPK-related signaling while YYH components may mitigate LGT-induced hepatotoxicity, exemplifying the TCM principle of enhancing therapeutic efficacy while reducing toxicity.

Keywords

Tripterygium wilfordii / Epimedium brevicornum / rheumatoid arthritis / hepatoprotection / synergistic effect / network pharmacology / molecular docking

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