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<p>Gain-of-function mutations of isocitrate dehydrogenase 1 (<i>IDH1</i>) lead to oncometabolite (<i>R</i>)-2-hydroxyglutarate production, contributing to the tumorigenesis of multiple human cancers. While fatty acid biosynthesis is critical for <i>IDH1</i>-mutant tumor growth, the underlying mechanisms remain unclear. Here, leveraging chemical probes and chemoproteomic profiling, we identified that oncogenic IDH1-R132H is uniquely autopalmitoylated at C269, which is not observed in wild-type IDH1. This modification responds to fatty acids and regulates R132H enzymatic activity by enhancing substrate and cofactor binding, as well as dimerization. Loss of C269 palmitoylation reverses IDH1-R132H-induced metabolic reprogramming and hypermethylation phenotypes and impairs cell transformation. Interestingly, C269 autopalmitoylation occurs within a hydrophobic pocket, targeted by a clinical <i>IDH1</i>-mutant inhibitor (LY3410738). Our study reveals that autopalmitoylation, conferred by the <i>IDH1</i><sup>R132H</sup> mutation, links fatty acid metabolism to the regulation of IDH1 mutant activity and represents a druggable vulnerability in <i>IDH1</i>-mutant cancers.</p><p></p>

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Autopalmitoylation of IDH1-R132H regulates its neomorphic activity in cancer cells

  • 期刊论文

  • 发表日期：

    2026年1月13日

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  • Lu Hu,
  • Jinyu Lin,
  • Liping Sun,
  • Alison M. Berezuk,
  • Katharine S. Tuttle,
  • Xing Zhu,
  • Hyuk-Soo Seo,
  • Sirano Dhe-Paganon,
  • Pan Li,
  • Yang Sun,
  • Lisheng Ni,
  • Jianan Zhang,
  • Dazhi Tan,
  • Hiroaki Wakimoto,
  • Daniel P. Cahill,
  • Xiaochen Bai,
  • Xuelian Luo,
  • John M. Asara,
  • Sriram Subramaniam,
  • Yibing Shan,
  • Xu Wu

摘要

Gain-of-function mutations of isocitrate dehydrogenase 1 (IDH1) lead to oncometabolite (R)-2-hydroxyglutarate production, contributing to the tumorigenesis of multiple human cancers. While fatty acid biosynthesis is critical for IDH1-mutant tumor growth, the underlying mechanisms remain unclear. Here, leveraging chemical probes and chemoproteomic profiling, we identified that oncogenic IDH1-R132H is uniquely autopalmitoylated at C269, which is not observed in wild-type IDH1. This modification responds to fatty acids and regulates R132H enzymatic activity by enhancing substrate and cofactor binding, as well as dimerization. Loss of C269 palmitoylation reverses IDH1-R132H-induced metabolic reprogramming and hypermethylation phenotypes and impairs cell transformation. Interestingly, C269 autopalmitoylation occurs within a hydrophobic pocket, targeted by a clinical IDH1-mutant inhibitor (LY3410738). Our study reveals that autopalmitoylation, conferred by the IDH1R132H mutation, links fatty acid metabolism to the regulation of IDH1 mutant activity and represents a druggable vulnerability in IDH1-mutant cancers.