The novel role of DUSP4 in suppressing ferroptosis and promoting cytotoxicity of CD8⁺ T cells in MSI colorectal cancer

Dongsheng Zhang ¹, Sheng Yang ^1,2, Hengjie Xu ^1,2

¹Department of General Surgery, Colorectal Institute of Nanjing Medical University, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
²The First School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.
³Department of General Surgery, Colorectal Institute of Nanjing Medical University, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China. wxw0213@njmu.edu.cn.
⁴The First School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, China. wxw0213@njmu.edu.cn.
⁵Department of General Surgery, Colorectal Institute of Nanjing Medical University, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China. sunyueming@njmu.edu.cn.
⁶Jiangsu Province Engineering Research Center of Colorectal Cancer Precision Medicine and Translational Medicine, Nanjing, Jiangsu, China. sunyueming@njmu.edu.cn.
⁷Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, China. sunyueming@njmu.edu.cn.
⁸The Affiliated Shuyang Hospital of Xuzhou Medical University, Suqian, Jiangsu, China. sunyueming@njmu.edu.cn.

⁰Department of General Surgery, Colorectal Institute of Nanjing Medical University, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.

British Journal of Cancer +

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August 22, 2025

View abstract on PubMed

Summary

Dual specificity phosphatase 4 (DUSP4) suppresses ferroptosis and enhances CD8+ T cell infiltration in microsatellite instable colorectal cancer (MSI CRC). This finding offers new therapeutic strategies for MSI CRC by targeting DUSP4 to improve immunotherapy effectiveness.

Area Of Science

Oncology
Immunology
Cell Biology

Background

Microsatellite instable (MSI) colorectal cancer (CRC) exhibits unique characteristics compared to microsatellite stable (MSS) CRC.
The role of ferroptosis in MSI CRC development is suspected but not fully understood.

Purpose Of The Study

To investigate the mechanisms by which ferroptosis influences MSI CRC.
To explore the regulatory role of Dual Specificity Phosphatase 4 (DUSP4) in ferroptosis and CD8+ T cell infiltration within MSI CRC.

Main Methods

Ferroptosis assessment using lipid peroxidation, malondialdehyde, 4-hydroxy-2-nonenal, and intracellular Fe2+ detection.
Phosphoproteomic analysis, cytokine array, and flow cytometry to study CD8+ T cell infiltration regulation.
Analysis of DUSP4, transferrin receptor (TFRC), c-MYC, cyclin-dependent kinase 7 (CDK7), and C-X-C Motif chemokine ligand 16 (CXCL16) expression and interactions.

Main Results

DUSP4 was found to suppress ferroptosis in MSI CRC cells by reducing lipid peroxidation and intracellular Fe2+ accumulation.
DUSP4 downregulated TFRC expression, which is transcriptionally regulated by c-MYC.
DUSP4 dephosphorylated CDK7, promoting CXCL16 expression and increasing CD8+ T cell infiltration.
A positive correlation between CD8+ T cell infiltration and DUSP4 expression in CRC tissues was observed.

Conclusions

DUSP4 functions as a negative regulator of ferroptosis in MSI CRC.
DUSP4 acts as a positive regulator of CD8+ T cell infiltration in MSI CRC.
Targeting DUSP4 and CDK7 may enhance the efficacy of immunotherapy in MSI CRC.

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