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<p>Chemotherapeutic efficacy in colorectal cancer (CRC) is primarily driven‌ by adaptive mechanisms that circumvent therapy-induced ferroptosis. Despite the established role of ROS-mediated lipid peroxidation in initiating ferroptosis, the molecular regulators enabling cancer cells to escape this iron-dependent demise remain elusive. Here, we ‌identify‌ Heterogeneous Nuclear Ribonucleoprotein C (HNRNPC) as a critical orchestrator of chemoresistance in CRC via metabolic reprogramming of ferroptosis pathways. ‌Clinically, elevated HNRNPC expression correlates with poor chemotherapy outcomes‌ by conferring resistance to irinotecan (CPT-11). Mechanistically, HNRNPC augments the Nrf2/SLC7A11 axis-associated transcript stability by shielding <i>Nrf2</i> and <i>SLC7A11</i> mRNAs from degradation machinery, thereby enhancing the longevity of their RNAs. Concurrently, HNRNPC forms a direct protein interactome with ferroptosis gatekeepers Nrf2 and SLC7A11, enforcing the post-translational stabilization of these cytoprotective effectors. This bimodal regulation establishes HNRNPC as a master ferroptosis suppressor that drives acquired chemoresistance through redox homeostasis reprogramming in colorectal carcinogenesis, thereby enhancing cellular redox buffering capability. This RNA–protein interaction amplifies the Nrf2/SLC7A11 signaling axis, which scavenges lethal lipid peroxides and attenuates CPT-11 cytotoxicity. Genetic depletion or pharmacological inhibition of HNRNPC restored ferroptotic vulnerability and resensitized CRC models to chemotherapy. Our findings establish HNRNPC as a post-transcriptional regulator of ferroptosis defense and reveal a therapeutic strategy for overcoming chemoresistance by co-targeting HNRNPC in CRC‌‌.</p>

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HNRNPC reprograms cancer metabolism to drive acquired chemoresistance in colorectal cancer by repressing of Nrf2/SLC7A11-dependent ferroptosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月10日

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  • Xiaojian Zhu,
  • Shanshan Lin,
  • Lingling Ruan,
  • Jianyong Xiong,
  • Dengke Yao,
  • Hongtao Wan,
  • Yanglin Chen,
  • Zhijiang Huang,
  • Weiming Qiu,
  • Dan Liu,
  • Bo Yi

摘要

Chemotherapeutic efficacy in colorectal cancer (CRC) is primarily driven‌ by adaptive mechanisms that circumvent therapy-induced ferroptosis. Despite the established role of ROS-mediated lipid peroxidation in initiating ferroptosis, the molecular regulators enabling cancer cells to escape this iron-dependent demise remain elusive. Here, we ‌identify‌ Heterogeneous Nuclear Ribonucleoprotein C (HNRNPC) as a critical orchestrator of chemoresistance in CRC via metabolic reprogramming of ferroptosis pathways. ‌Clinically, elevated HNRNPC expression correlates with poor chemotherapy outcomes‌ by conferring resistance to irinotecan (CPT-11). Mechanistically, HNRNPC augments the Nrf2/SLC7A11 axis-associated transcript stability by shielding Nrf2 and SLC7A11 mRNAs from degradation machinery, thereby enhancing the longevity of their RNAs. Concurrently, HNRNPC forms a direct protein interactome with ferroptosis gatekeepers Nrf2 and SLC7A11, enforcing the post-translational stabilization of these cytoprotective effectors. This bimodal regulation establishes HNRNPC as a master ferroptosis suppressor that drives acquired chemoresistance through redox homeostasis reprogramming in colorectal carcinogenesis, thereby enhancing cellular redox buffering capability. This RNA–protein interaction amplifies the Nrf2/SLC7A11 signaling axis, which scavenges lethal lipid peroxides and attenuates CPT-11 cytotoxicity. Genetic depletion or pharmacological inhibition of HNRNPC restored ferroptotic vulnerability and resensitized CRC models to chemotherapy. Our findings establish HNRNPC as a post-transcriptional regulator of ferroptosis defense and reveal a therapeutic strategy for overcoming chemoresistance by co-targeting HNRNPC in CRC‌‌.