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Article Abstract
Background: Microsatellite instable (MSI) colorectal cancer (CRC) has distinct features that distinguish it from microsatellite stable CRC. While ferroptosis may play a role in the development of MSI CRC, its mechanisms remain unclear.
Methods: Ferroptosis was assessed via the detection of lipid peroxidation, malondialdehyde, 4-hydroxy-2-nonenal, and intracellular Fe2, etc. Phosphoproteomic analysis, cytokine array, and flow cytometry were performed to explore the regulation of CD8 T cell infiltration.
Results: Dual specificity phosphatase 4 (DUSP4) suppressed ferroptosis in MSI CRC cells by reducing lipid peroxidation and inhibiting intracellular Fe2 accumulation. Mechanistic studies showed that DUSP4 downregulated the expression of transferrin receptor (TFRC), which was transcriptionally regulated by c-MYC. In addition, a positive correlation was observed between the infiltration of CD8 T cells in CRC tissues and the expression of DUSP4 in cancer cells. Mechanistically, DUSP4 dephosphorylated cyclin-dependent kinase 7 (CDK7) and promoted C-X-C Motif chemokine ligand 16 (CXCL16) expression, resulting in an increased infiltration of CD8 T cells. Importantly, the combination of a CDK7 inhibitor and anti-programmed cell death protein-1 therapy demonstrated a synergistic therapeutic effect in MSI CRC.
Conclusion: DUSP4 acts as a negative regulator of ferroptosis and a positive regulator of CD8 T cell infiltration in MSI CRC.
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