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<p>Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, necessitating novel therapeutic strategies. This study demonstrates that high-dose sodium selenite (Na₂SeO₃) induces ferroptosis in CRC cells by directly targeting the Nrf2/Gpx4 antioxidant pathway.&#xa0;Critically, molecular docking analysis confirmed strong binding interactions between Na₂SeO₃ and both the Nrf2 and Gpx4 proteins,&#xa0;suggesting a direct mechanistic link. Clinical samples from CRC patients revealed significantly decreased serum selenium levels, which correlated negatively with tumor markers (CEA, CA199, CA125) and positively with nutritional indicators (hemoglobin, albumin). Immunohistochemistry confirmed elevated Gpx4 and Nrf2 expression in tumor tissues. In vitro experiments using HCT116 cells showed that Na₂SeO₃ treatment inhibited proliferation, increased intracellular Fe<sup>2</sup>⁺, MDA, and ROS levels, and reduced mitochondrial membrane potential. Western blotting further revealed the downregulation of Nrf2 and Gpx4 proteins upon selenium treatment. Our research findings indicate that sodium selenite may induce ferroptosis by regulating the Nrf2/Gpx4 axis, highlighting its potential as a dual nutrient and pharmacological drug for the treatment of CRC.</p>

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Selenium Induces Ferroptosis in Colorectal Cancer Cells via Direct Interaction with Nrf2 and Gpx4

  • 期刊论文

  • 发表日期：

    2025年11月9日

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  • Mengxue Zhao,
  • Mengyao Xu,
  • Wei Zhang,
  • Mingye Tang,
  • Shan Ji,
  • Jie Shi

摘要

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, necessitating novel therapeutic strategies. This study demonstrates that high-dose sodium selenite (Na₂SeO₃) induces ferroptosis in CRC cells by directly targeting the Nrf2/Gpx4 antioxidant pathway. Critically, molecular docking analysis confirmed strong binding interactions between Na₂SeO₃ and both the Nrf2 and Gpx4 proteins, suggesting a direct mechanistic link. Clinical samples from CRC patients revealed significantly decreased serum selenium levels, which correlated negatively with tumor markers (CEA, CA199, CA125) and positively with nutritional indicators (hemoglobin, albumin). Immunohistochemistry confirmed elevated Gpx4 and Nrf2 expression in tumor tissues. In vitro experiments using HCT116 cells showed that Na₂SeO₃ treatment inhibited proliferation, increased intracellular Fe2⁺, MDA, and ROS levels, and reduced mitochondrial membrane potential. Western blotting further revealed the downregulation of Nrf2 and Gpx4 proteins upon selenium treatment. Our research findings indicate that sodium selenite may induce ferroptosis by regulating the Nrf2/Gpx4 axis, highlighting its potential as a dual nutrient and pharmacological drug for the treatment of CRC.