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<p>This study aimed to determine the effect of Artesunate (ART) on oxaliplatin-resistance of colorectal cancer (CRC) and the underlying mechanism. CRC parent and oxaliplatin-resistance cells were induced ferroptosis by ART, overexpression or silence of CDK5 and Nrf2 was conducted on CRC cells, and the function of cells were tested. The protein location, binding effect, protein–protein interaction, ART–CDK5 interaction were determined. Mice model was used to validated the effect of ART on CRC cells. ART induces ferroptosis and inhibits oxaliplatin-resistance of CRC cells. CDK5 promoted the viability, invasive, migration of CRC cells, but did not lead to increases cell apoptosis. CDK5 was associated with ferroptosis and oxaliplatin-resistance of CRC cells, and ART binding and inhibited the expression of CDK5. CDK5 inhibit CRC cells ferroptosis and promote oxaliplatin-resistance; CDK5 binding to Nrf2, increased stability and promote translocation of Nrf2 from cytosol to nuclear. By combination of overexpression of CDK5 and the overexpression or silence of Nrf2 in CRC cells, we found that CDK5 inhibited ferroptosis of CRC cells and enhance resistance to oxaliplatin via Nrf2/GPX4 pathway. The in vivo experiments exhibited that combination of ART and sh-CDK5 reduce the growth of tumors with low toxicity in xenograft models, and reduced Nrf2 and GPX4 expression. ART induced ferroptosis thereby overcomes oxaliplatin-resistance of CRC cells, this effect was via modulating the CDK5/Nrf2/GPX4 pathway. These findings highlight CDK5 as a critical regulator of redox homeostasis in CRC and the therapeutic potential of ART in treating chemoresistant tumors.</p> Graphical abstract <p></p> <p>The present study demonstrate that ART was able to induce ferroptosis via binding and regulation of CDK5, and CDK5 modulates the expression of Nrf2, thereby inhibited biological function of CRC cells and attenuates oxaliplatin-resistance of the cells, this effect was via orchestrating the Nrf2/GPX4 pathway.</p>

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Artesunate overcomes oxaliplatin resistance in colorectal cancer by inducing ferroptosis through inhibition of the CDK5/Nrf2/GPX4 pathway

  • 期刊论文

  • 发表日期：

    2026年5月24日

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  • Feng Lv,
  • Xiao-huan Li,
  • Si-qi Li,
  • Hao-wei Deng,
  • Hao-tang Wei,
  • Ke-zhi Li,
  • Ming-zhi Xie,
  • Li-ye Xie,
  • Shu-fang Ning,
  • Bang-li Hu

摘要

This study aimed to determine the effect of Artesunate (ART) on oxaliplatin-resistance of colorectal cancer (CRC) and the underlying mechanism. CRC parent and oxaliplatin-resistance cells were induced ferroptosis by ART, overexpression or silence of CDK5 and Nrf2 was conducted on CRC cells, and the function of cells were tested. The protein location, binding effect, protein–protein interaction, ART–CDK5 interaction were determined. Mice model was used to validated the effect of ART on CRC cells. ART induces ferroptosis and inhibits oxaliplatin-resistance of CRC cells. CDK5 promoted the viability, invasive, migration of CRC cells, but did not lead to increases cell apoptosis. CDK5 was associated with ferroptosis and oxaliplatin-resistance of CRC cells, and ART binding and inhibited the expression of CDK5. CDK5 inhibit CRC cells ferroptosis and promote oxaliplatin-resistance; CDK5 binding to Nrf2, increased stability and promote translocation of Nrf2 from cytosol to nuclear. By combination of overexpression of CDK5 and the overexpression or silence of Nrf2 in CRC cells, we found that CDK5 inhibited ferroptosis of CRC cells and enhance resistance to oxaliplatin via Nrf2/GPX4 pathway. The in vivo experiments exhibited that combination of ART and sh-CDK5 reduce the growth of tumors with low toxicity in xenograft models, and reduced Nrf2 and GPX4 expression. ART induced ferroptosis thereby overcomes oxaliplatin-resistance of CRC cells, this effect was via modulating the CDK5/Nrf2/GPX4 pathway. These findings highlight CDK5 as a critical regulator of redox homeostasis in CRC and the therapeutic potential of ART in treating chemoresistant tumors.

Graphical abstract

The present study demonstrate that ART was able to induce ferroptosis via binding and regulation of CDK5, and CDK5 modulates the expression of Nrf2, thereby inhibited biological function of CRC cells and attenuates oxaliplatin-resistance of the cells, this effect was via orchestrating the Nrf2/GPX4 pathway.