2. Academic Validation
  3. Targeting YRDC blocks codon-biased FABP7 translation and lipid droplet formation to overcome chemoresistance in glioblastoma

Targeting YRDC blocks codon-biased FABP7 translation and lipid droplet formation to overcome chemoresistance in glioblastoma

  • Oncogene. 2026 Jun;45(22):2155-2170. doi: 10.1038/s41388-026-03801-0.
Yuchao Zhang # 1 2 3,  Xuesong Yang # 1 2 3,  Xixi Li # 1 2 3,  Chen Zheng # 1 2 3,  Xuechao Zeng # 1 2 3,  Junju Chen 1 2 3,  Mingpu Gao 1 2 3,  Long Cheng 1 2 3,  Zhenyan Xu 1 2 3,  Lanjie Chen 1 2 3,  Yixin Gao 1 2 3,  Jian Zhong 1 2 3,  Nunu Huang 1 2 3,  Xuesong Liu 4 5 6,  Kejun He 7 8 9,  Nu Zhang 10 11 12,  Xujia Wu 13 14 15
Affiliations

Affiliations

  • 1 Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 2 Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, China.
  • 3 Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 4 Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. [email protected].
  • 5 Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, China. [email protected].
  • 6 Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. [email protected].
  • 7 Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. [email protected].
  • 8 Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, China. [email protected].
  • 9 Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. [email protected].
  • 10 Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. [email protected].
  • 11 Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, China. [email protected].
  • 12 Department of Neurosurgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China. [email protected].
  • 13 Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. [email protected].
  • 14 Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, China. [email protected].
  • 15 Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. [email protected].
  • # Contributed equally.
PMID: 42014887 DOI: 10.1038/s41388-026-03801-0
Abstract

Dysregulation of transfer RNA (tRNA) modification and reprogramming of codon-biased translation are commonly associated with Cancer initiation and progression. However, their roles in chemoresistance and tumor recurrence remain poorly understood, especially in glioblastoma (GBM). This study establishes the tRNA-modifying enzyme YrdC N6-Threonylcarbamoyltransferase Domain Containing (YRDC) as a key mediator of temozolomide (TMZ) resistance in GBM. YRDC catalyzes the formation of N6-threonylcarbamoyladenosine (t6A) on ANN-decoding tRNAs (A denotes adenosine, and N denotes any nucleotide). YRDC expression is elevated in TMZ-resistant models and recurrent GBM, correlating with poor patient prognosis. Mechanistically, YRDC drives ANN codon-biased translation of target mRNAs, most notably encoding the fatty acid-binding protein FABP7. Elevated FABP7 induces lipid droplet accumulation, which sequesters TMZ-induced Reactive Oxygen Species to mitigate oxidative stress and confer chemoresistance. Targeting this axis, we developed HY-Q66655, a novel blood-brain-barrier-penetrant YRDC inhibitor identified via virtual screening. HY-Q66655 directly inhibits YRDC, suppresses FABP7 translation, depletes lipid droplets, and acts synergistically with TMZ to inhibit tumor growth in vitro and in patient-derived orthotopic xenografts. The YRDC/FABP7 pathway is clinically associated with GBM recurrence, and HY-Q66655 demonstrates broad-spectrum anti-tumor activity across malignancies, revealing a tRNA modification-dependent mechanism and a potential therapeutic strategy.

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