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

## TL;DR

This study explores combining mesenchymal stem cells and silybin to treat rheumatoid arthritis by targeting the ICOS/ICOSL pathway and reducing inflammation.

## Contribution

A novel combination therapy using UC-MSCs and silybin to overcome treatment resistance in RA via the ICOS/ICOSL-PI3K/AKT/mTOR pathway.

## Key findings

- Elevated ICOS in RA patients correlates with poor UC-MSC treatment response.
- Silybin inhibits the ICOS/ICOSL-PI3K/AKT/mTOR pathway, reducing inflammation.
- Combining silybin with UC-MSCs improves immunoregulation in RA models.

## Abstract

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.

In our study, UC‐MSCs showed a poor immunoregulatory effect for RA patients with upregulated inducible costimulator (ICOS) in PBMCs. And we identified the ICOS ligand (ICOSL) of UC‐MSCs combined with ICOS of RA patients, activating Phosphatidylinositol 3‐kinase / Protein kinase B / Mammalian target of rapamycin (PI3K/AKT/mTOR). The CM5 chip was installed according to the standard operating procedures of the Biacore 8k instrument prior to ligand immobilization. pathway and triggering the subsequent inflammatory cascade reaction. Besides, silybin (SB) could directly bind to ICOS in PBMCs of RA patients competing with UC‐MSCs. Finally, we found a combination of UC‐MSCs and SB alleviated RA better in the CIA model, providing a new approach for treating RA.