A Potential Approach of Mesenchymal Stem Cells Combined Silybin for Synergistic Treatment in Rheumatoid Arthritis via ICOS/ICOSL

Achieving clinical remission in rheumatoid arthritis (RA) remains a significant challenge in current therapeutic strategies. While transplantation of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) has shown promising outcomes, therapeutic responses vary considerably among patients. In this study, we characterized the immune profiles of nonresponders and identified elevated expression of inducible costimulator (ICOS) in peripheral immune cells as a critical barrier to effective treatment. This upregulation, combined with the presence of ICOS ligand (ICOSL) on UC-MSCs, activated T cells to secrete inflammatory cytokines through the Phosphatidylinositol 3-kinase / Protein kinase B / Mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. To overcome this limitation, we identified silybin as a potential adjunctive agent. Further investigations demonstrated that silybin acts as a competitive binding inhibitor, effectively targeting the PI3K/AKT/mTOR pathway and reducing downstream cytokine release. The combined application of silybin and UC-MSCs significantly enhanced immunoregulatory effects, as validated through in vitro analyses with patient-derived samples and in vivo experiments using a collagen-induced arthritis mouse model. This study highlights a novel, personalized therapeutic approach for RA, offering insights into improving clinical outcomes through targeted interventions.