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<p>Anaplastic thyroid cancer (ATC) is an aggressive endocrine malignancy characterized by rapid progression and limited therapeutic options. Ferritinophagy, a selective autophagic process mediated by NCOA4, regulates intracellular iron homeostasis. Here, we demonstrate that the prolyl isomerase Pin1 drives ATC progression by suppressing NCOA4-dependent ferritinophagy. Mechanistically, Pin1 recognizes phosphorylated NCOA4 through its substrate-binding WW domain. CDK2 phosphorylates NCOA4 at Ser572, creating a binding site for Pin1. This interaction promotes K29/K48-linked polyubiquitination and proteasomal degradation of NCOA4, thereby blocking ferritinophagy, lowering intracellular Fe²⁺ and lipid peroxidation, and ultimately suppressing ferroptosis. Pin1 knockdown or treatment with the pharmacological Pin1 inhibitor KPT-6566 stabilizes NCOA4, enhances ferritinophagy, and triggers ferroptosis, markedly restraining ATC growth both in vitro and in vivo. These findings identify Pin1 as a previously unrecognized suppressor of ferroptosis through NCOA4-dependent ferritinophagy and support Pin1 inhibition as a potential therapeutic strategy for ATC.</p>

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Pin1 targets phosphorylated NCOA4 for K29/K48-linked ubiquitination to suppress ferritinophagy and ferroptosis in anaplastic thyroid cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月1日

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  • Zicheng Sun,
  • Fan Bai,
  • Mingwei Liang,
  • Hannah Xiaoyan Hui,
  • Huazhen Xu,
  • Zhaoxi Zhang,
  • Xin Liu,
  • Peng Hu,
  • Weiming Lv,
  • Rui Ge,
  • Jie Li

摘要

Anaplastic thyroid cancer (ATC) is an aggressive endocrine malignancy characterized by rapid progression and limited therapeutic options. Ferritinophagy, a selective autophagic process mediated by NCOA4, regulates intracellular iron homeostasis. Here, we demonstrate that the prolyl isomerase Pin1 drives ATC progression by suppressing NCOA4-dependent ferritinophagy. Mechanistically, Pin1 recognizes phosphorylated NCOA4 through its substrate-binding WW domain. CDK2 phosphorylates NCOA4 at Ser572, creating a binding site for Pin1. This interaction promotes K29/K48-linked polyubiquitination and proteasomal degradation of NCOA4, thereby blocking ferritinophagy, lowering intracellular Fe²⁺ and lipid peroxidation, and ultimately suppressing ferroptosis. Pin1 knockdown or treatment with the pharmacological Pin1 inhibitor KPT-6566 stabilizes NCOA4, enhances ferritinophagy, and triggers ferroptosis, markedly restraining ATC growth both in vitro and in vivo. These findings identify Pin1 as a previously unrecognized suppressor of ferroptosis through NCOA4-dependent ferritinophagy and support Pin1 inhibition as a potential therapeutic strategy for ATC.