Astilbin: a novel therapeutic strategy for bone destruction in rheumatoid arthritis.

BACKGROUND: Bone destruction constitutes the primary cause of disability in rheumatoid arthritis (RA). Herbal medicines feature unique multi-target advantages, rendering them promising therapeutic candidates for attenuating RA-associated bone damage. OBJECTIVE: This study aimed to investigate the therapeutic efficacy and underlying mechanisms of astilbin, a core bioactive flavonoid extracted from Tufuling (Smilax glabra), against bone destruction in RA. METHODS: A CIA mouse model was established via tail vein injection of type II collagen. Micro-CT, HE staining and TRAP staining were applied to evaluate the inhibitory and therapeutic effects of astilbin on RA bone destruction. Network pharmacology and bioinformatics analyses were performed to screen the potential targets and signaling pathways of astilbin for RA treatment. Mendelian randomization analysis was further conducted to genetically validate the correlation between candidate genes and RA. Molecular docking was utilized to calculate binding energies between astilbin and core pathogenic targets of RA. Immunofluorescence, elisa, WB and qPCR were adopted to verify the key targets and anti-inflammatory activity of astilbin in ameliorating RA bone erosion. RESULTS: In vivo animal experiments demonstrated that astilbin alleviated RA bone destruction, suppressed synovial hyperplasia, inhibited osteoclastogenesis, and downregulated the expression of pro-inflammatory cytokines. Network pharmacology identified MAPK3, MAPK1, PTPN11, HSP90AA1, STAT1 and SRC as the core therapeutic targets of astilbin against RA. KEGG enrichment analysis revealed that the anti-RA effects of astilbin were tightly associated with the MAPK signaling pathways and so on. Mendelian randomization analysis further verified a strong genetic correlation between the apoptotic protein MAPK3 and RA. Molecular docking results exhibited favorable binding affinity between astilbin and key pathogenic targets of RA. CONCLUSION: Astilbin may exert multiple pharmacological effects including anti-inflammation, inhibition of osteoclast activation, improvement of bone microarchitecture and alleviation of bone destruction in RA via regulating the MAPK signaling pathway, and it exhibits favorable safety in vivo.