This study explores the molecular mechanisms of triptolide (TP) in treating rheumatoid arthritis (RA) and reveals the dialectical unity between its therapeutic effects and toxic side effects.Through transcriptome sequencing (RNA-seq),network pharmacology,and toxicology analysis,we uncover the therapeutic mechanisms of TP for RA and its associated toxicity.Firstly,differential expression genes (DEGs) were identified in fibroblast-like synoviocytes (FLS) treated with TP via RNA-seq.Targets related to RA,as well as hepatic toxicity,renal toxicity,and reproductive toxicity,were identified by combining GeneCards,OMIM,and CTD databases.A protein-protein interaction (PPI) network was then constructed to screen for key therapeutic targets of TP.Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed,followed by molecular docking verification.The study identified key targets involved in TP′s therapeutic effects on RA and its toxicity,including tumor protein p53 (TP53),tumor necrosis factor (TNF),and interleukin-1β (IL-1β),which are involved in several signaling pathways such as TNF,nuclear factor-κB (NF-κB),janus kinase-signal transducer and activator of transcription (JAK-STAT),mitogen-activated protein kinase (MAPK),and forkhead box O (FoxO).RNA-seq results indicated that TP significantly regulated the expression of target genes such as TP53,TNF,and IL-1β,with statistically significant differences.In summary,TP demonstrates both therapeutic efficacy and accompanying toxic effects in the treatment of RA,with the mechanisms being interrelated,reflecting the dialectical unity of efficacy and toxicity.