2. Academic Validation
  3. Autopalmitoylation of IDH1-R132H regulates its neomorphic activity in cancer cells

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

  • Nat Chem Biol. 2026 Jan 13. doi: 10.1038/s41589-025-02131-8.
Lu Hu 1,  Jinyu Lin 2,  Liping Sun 2,  Alison M Berezuk 3,  Katharine S Tuttle 3,  Xing Zhu 3,  Hyuk-Soo Seo 4 5,  Sirano Dhe-Paganon 4 5,  Pan Li 6,  Yang Sun 7 6,  Lisheng Ni 8,  Jianan Zhang 7,  Dazhi Tan 9,  Hiroaki Wakimoto 10,  Daniel P Cahill 10,  Xiaochen Bai 8,  Xuelian Luo 8,  John M Asara 11,  Sriram Subramaniam 3,  Yibing Shan 12 13,  Xu Wu 14
Affiliations

Affiliations

  • 1 Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. [email protected].
  • 2 iHuman Institute, Shanghai Tech University, Shanghai, China.
  • 3 Department of Biochemistry & Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada.
  • 4 Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 5 Chemical Biology Program, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 6 Cancer Institute, Xuzhou Medical University, Xuzhou, China.
  • 7 Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
  • 8 Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 9 Antidote Health Foundation for Cure of Cancer, Cambridge, MA, USA.
  • 10 Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 11 Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  • 12 iHuman Institute, Shanghai Tech University, Shanghai, China. [email protected].
  • 13 Antidote Health Foundation for Cure of Cancer, Cambridge, MA, USA. [email protected].
  • 14 Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. [email protected].
PMID: 41530531 DOI: 10.1038/s41589-025-02131-8
Abstract

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.

Figures
Products