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Background <p>Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic synovitis, primarily affecting symmetric small joints. Deucravacitinib, a novel oral highly selective tyrosine kinase 2 (TYK2) inhibitor, has shown promise in treating various immune-mediated diseases. This study aimed to explore the therapeutic effects and underlying mechanisms of deucravacitinib in RA.</p> Methods <p>The anti-proliferative effects of deucravacitinib were assessed using the CCK-8 assay, while its pro-apoptotic activity in MH7A cells was evaluated via flow cytometry. Cell wound healing assay and transwell assays were employed to determine the migration and invasive capabilities of MH7A cells. RNA sequencing (RNA-seq) was conducted to identify differentially expressed genes following deucravacitinib treatment. Network pharmacology and molecular docking analyses were utilized to predict potential anti-arthritic targets. The impact of deucravacitinib on the TYK2/STAT3 (signal transducer and activator of transcription) and PI3K(phosphoinositide3-kinase)/AKT(protein kinases B) signaling pathways was investigated. In vivo, a collagen-induced arthritis (CIA) mouse model was treated with low-dose deucravacitinib (5&#xa0;mg/kg/d) for 21 days, and its anti-arthritic effects were evaluated.</p> Results <p>In vitro, deucravacitinib significantly inhibited MH7A cell proliferation and induced apoptosis, while also reducing cell migration and invasion. Mechanistically, deucravacitinib upregulated Bax (Bcl-2-associated X protein) expression and downregulated Bcl-2 (B-cell lymphoma 2), MMP-2(Matrix Metalloproteinase-2), and MMP-9(Matrix Metalloproteinase-9) mRNA levels, likely through inhibition of the TYK2/STAT3 and PI3K/AKT pathways. In vivo, deucravacitinib alleviated toe swelling, reduced arthritis scores, and decreased mRNA levels of Bcl-2, MMP-2, and MMP-9 in CIA mice. Histopathological analysis revealed improved joint integrity and reduced bone erosion.</p> Conclusion <p>Deucravacitinib demonstrates significant anti-arthritic potential by inhibiting synovial fibroblast proliferation, migration, and invasion while promoting apoptosis. These effects are mediated through suppression of the TYK2/STAT3 and PI3K/AKT signaling pathways, suggesting its promise as a therapeutic agent for RA.</p>

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Deucravacitinib Inhibits Synovial Fibroblast Activation Via TYK2/STAT3 and PI3K/Akt Signaling Pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月11日

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  • Zechao Qu,
  • Jing Wang,
  • Xiaohao Wang,
  • Lingfei Mo,
  • Hanchao Li,
  • Xinyi Liu,
  • Xiawei Chai,
  • Liang Yan,
  • Yuanyuan Li

摘要

Background

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic synovitis, primarily affecting symmetric small joints. Deucravacitinib, a novel oral highly selective tyrosine kinase 2 (TYK2) inhibitor, has shown promise in treating various immune-mediated diseases. This study aimed to explore the therapeutic effects and underlying mechanisms of deucravacitinib in RA.

Methods

The anti-proliferative effects of deucravacitinib were assessed using the CCK-8 assay, while its pro-apoptotic activity in MH7A cells was evaluated via flow cytometry. Cell wound healing assay and transwell assays were employed to determine the migration and invasive capabilities of MH7A cells. RNA sequencing (RNA-seq) was conducted to identify differentially expressed genes following deucravacitinib treatment. Network pharmacology and molecular docking analyses were utilized to predict potential anti-arthritic targets. The impact of deucravacitinib on the TYK2/STAT3 (signal transducer and activator of transcription) and PI3K(phosphoinositide3-kinase)/AKT(protein kinases B) signaling pathways was investigated. In vivo, a collagen-induced arthritis (CIA) mouse model was treated with low-dose deucravacitinib (5 mg/kg/d) for 21 days, and its anti-arthritic effects were evaluated.

Results

In vitro, deucravacitinib significantly inhibited MH7A cell proliferation and induced apoptosis, while also reducing cell migration and invasion. Mechanistically, deucravacitinib upregulated Bax (Bcl-2-associated X protein) expression and downregulated Bcl-2 (B-cell lymphoma 2), MMP-2(Matrix Metalloproteinase-2), and MMP-9(Matrix Metalloproteinase-9) mRNA levels, likely through inhibition of the TYK2/STAT3 and PI3K/AKT pathways. In vivo, deucravacitinib alleviated toe swelling, reduced arthritis scores, and decreased mRNA levels of Bcl-2, MMP-2, and MMP-9 in CIA mice. Histopathological analysis revealed improved joint integrity and reduced bone erosion.

Conclusion

Deucravacitinib demonstrates significant anti-arthritic potential by inhibiting synovial fibroblast proliferation, migration, and invasion while promoting apoptosis. These effects are mediated through suppression of the TYK2/STAT3 and PI3K/AKT signaling pathways, suggesting its promise as a therapeutic agent for RA.