Molecular mechanisms of herbal medicines and bioactive compounds in rheumatoid arthritis: a comprehensive network pharmacology perspective

Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease characterized by persistent synovial inflammation, progressive joint distruction, and systemic complications. Owing to the multifactorial nature of RA, therapies targeting a single molecular pathway often provide incomplete disease control and may be associated with long-term adverse effects. Network pharmacology has emerged as a powerful system-level approach that integrates bioinformatics, multi-omics datasets, molecular docking, and experimental validation to unravel the complex interactions among bioactive compounds, molecular targets, and signaling pathways. This review highlights the novel application of network pharmacology in deciphering the multi-target mechanisms of herbal medicines for RA and summarizes recent advances in this rapidly evolving field. Particular emphasis is placed on key pathogenic pathways, including NF-κB, PI3K/Akt, MAPK, JAK/STAT, NLRP3 inflammasome activation, oxidative stress responses, angiogenesis, and immune-cell dysregulation. Representative phytochemicals, such as quercetin, kaempferol, luteolin, triptolide, and berberine, are discussed for their ability to modulate inflammatory responses, fibroblast-like synoviocyte activation, macrophage polarization, and osteoclastogenesis through coordinated regulation of multiple signaling networks. Importantly, this review underscores the translational significance of network pharmacology as a bridge between traditional herbal medicine and modern drug discovery, facilitating target prioritization, mechanism-based validation, and the rational development of multi-target therapeutics for RA. Collectively, network pharmacology provides a robust framework for the mechanistic interpretation of herbal medicines and offers a promising opportunity to accelerate the discovery and clinical translation of safer, more effective therapies for RA.