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<p>Oxaliplatin resistance remains a major challenge in colorectal cancer (CRC) treatment. We investigated the FBXL5/IREB2/TFRC axis in ferroptosis-mediated resistance reversal. Bioinformatics analysis identified IREB2 as co-expressed in oxaliplatin resistance and ferroptosis pathways. Clinical samples revealed elevated iron metabolism in resistant CRC tissues. In vitro, FBXL5 knockdown in oxaliplatin-resistant cells (HCT-116/OXA) upregulated IREB2/TFRC, increased Fe²⁺/MDA, and reduced viability/proliferation. Combining oxaliplatin with ferroptosis inducer Erastin enhanced cell death, reversed by ferroptosis inhibitor Ferrostatin-1. Our findings demonstrate that targeting FBXL5 disrupts iron homeostasis, triggers ferroptosis, and overcomes oxaliplatin resistance in CRC.</p>

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Targeting FBXL5 to induce ferroptosis and reverse oxaliplatin resistance in iron-rich colorectal cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月24日

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  • Miaomiao Wang,
  • Ruizhe Zhang,
  • Shuang He,
  • Feifei Wen,
  • Xiaojie Yu,
  • Xiaoyang Xu,
  • Yangyang Li,
  • Shuhua Wu

摘要

Oxaliplatin resistance remains a major challenge in colorectal cancer (CRC) treatment. We investigated the FBXL5/IREB2/TFRC axis in ferroptosis-mediated resistance reversal. Bioinformatics analysis identified IREB2 as co-expressed in oxaliplatin resistance and ferroptosis pathways. Clinical samples revealed elevated iron metabolism in resistant CRC tissues. In vitro, FBXL5 knockdown in oxaliplatin-resistant cells (HCT-116/OXA) upregulated IREB2/TFRC, increased Fe²⁺/MDA, and reduced viability/proliferation. Combining oxaliplatin with ferroptosis inducer Erastin enhanced cell death, reversed by ferroptosis inhibitor Ferrostatin-1. Our findings demonstrate that targeting FBXL5 disrupts iron homeostasis, triggers ferroptosis, and overcomes oxaliplatin resistance in CRC.