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<p>Cancer cells reprogramme translation and metabolism to fuel tumorigenesis. Here, we show that hepatocellular carcinoma (HCC) paradoxically maintains low tyrosine levels despite increased uptake and reduced metabolism, redirecting tyrosine to translation via MYC-driven upregulation of tyrosyl-tRNA synthetase 1 (YARS1) and tRNA-Tyr<sup>GUA</sup>. Restricting tyrosine translation availability (RTTA) via dietary limitation, YARS1/tRNA-Tyr<sup>GUA</sup> ablation, tyrosine degradation (TAL), or YARS1 inhibition (tyrosinol) disturbs this adaptation, leading to the mitigation of tumorigenesis and extension of survival. Mechanistically, RTTA reduces tyrosine codon-dependent translation of mitochondrial complex I subunit NDUFB8 and lipid regulator SCD1, causing complex I misassembly, oxidative phosphorylation failure, and lipid peroxidation-induced ferroptosis. Genome-wide CRISPR screening identifies that loss of GPX4 and BCL2 by genetic manipulation or pharmacological treatment enhances the ability of RTTA to inhibit hepatocellular carcinogenesis. Our findings establish RTTA as a therapeutic strategy targeting tyrosine dependency and highlight combinatorial targeting of translation-metabolism crosstalk and ferroptosis pathways in liver cancer.</p>

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Targeting tRNA-dependent tyrosine usage unveils a metabolic vulnerability in hepatocellular carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月6日

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  • Hongli Zhang,
  • Zixuan Wang,
  • Yiqi Zhao,
  • Xiya Deng,
  • Jian Zhang,
  • Fei Shang,
  • Hongjie Zhang,
  • Yan Liu,
  • Hongbo Wang,
  • Yating Yang,
  • Huiyu Lin,
  • Bo Zhang,
  • Ce Liu,
  • Fan Guo,
  • Ruolin Zhang,
  • Qipeng Yuan,
  • Yue Feng,
  • Shi-Zhong Luo,
  • Wei-Dong Chen,
  • Yan-Dong Wang

摘要

Cancer cells reprogramme translation and metabolism to fuel tumorigenesis. Here, we show that hepatocellular carcinoma (HCC) paradoxically maintains low tyrosine levels despite increased uptake and reduced metabolism, redirecting tyrosine to translation via MYC-driven upregulation of tyrosyl-tRNA synthetase 1 (YARS1) and tRNA-TyrGUA. Restricting tyrosine translation availability (RTTA) via dietary limitation, YARS1/tRNA-TyrGUA ablation, tyrosine degradation (TAL), or YARS1 inhibition (tyrosinol) disturbs this adaptation, leading to the mitigation of tumorigenesis and extension of survival. Mechanistically, RTTA reduces tyrosine codon-dependent translation of mitochondrial complex I subunit NDUFB8 and lipid regulator SCD1, causing complex I misassembly, oxidative phosphorylation failure, and lipid peroxidation-induced ferroptosis. Genome-wide CRISPR screening identifies that loss of GPX4 and BCL2 by genetic manipulation or pharmacological treatment enhances the ability of RTTA to inhibit hepatocellular carcinogenesis. Our findings establish RTTA as a therapeutic strategy targeting tyrosine dependency and highlight combinatorial targeting of translation-metabolism crosstalk and ferroptosis pathways in liver cancer.