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<p>S-palmitoylation, a reversible post-translational modification regulates protein stability and cellular functions, yet its role in glutamine metabolism remains unclear. Here, we show that ZDHHC14 as the key palmitoyltransferase catalyzing ASCT2 palmitoylation at conserved Cys39 and Cys48 residues, promoting lysosomal degradation of this glutamine transporter, whereas ABHD17B functions as a depalmitoylase to stabilize ASCT2. Mechanistically, glutamine deprivation activates JNK1, which directly phosphorylates ZDHHC14 at Thr440 residue, triggering its degradation and thereby enhancing ASCT2 stability. Importantly, combination of JNK and ASCT2 inhibitors synergistically inhibits glutamine metabolism and tumor growth in vivo. These findings reveal a phosphorylation-palmitoylation axis linking JNK-mediated ASCT2 palmitoylation and glutamine metabolism, offering a potential therapeutic strategy for non-small cell lung cancer.</p>

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ASCT2 palmitoylation regulated by JNK1-ZDHHC14 axis orchestrates glutamine metabolism and NSCLC progression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月24日

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  • Xingyu Chen,
  • Zihao Ke,
  • Shihui Wei,
  • Jiajin Chen,
  • Ke Zhu,
  • Jiaqi Xu,
  • Yun Zhao,
  • Mengyuan Cen,
  • Yan Jin,
  • Zhilei Pan,
  • Juan Xiong,
  • Ying Chen,
  • Chenfang Dong,
  • Qianhua Cao,
  • Chao Cao

摘要

S-palmitoylation, a reversible post-translational modification regulates protein stability and cellular functions, yet its role in glutamine metabolism remains unclear. Here, we show that ZDHHC14 as the key palmitoyltransferase catalyzing ASCT2 palmitoylation at conserved Cys39 and Cys48 residues, promoting lysosomal degradation of this glutamine transporter, whereas ABHD17B functions as a depalmitoylase to stabilize ASCT2. Mechanistically, glutamine deprivation activates JNK1, which directly phosphorylates ZDHHC14 at Thr440 residue, triggering its degradation and thereby enhancing ASCT2 stability. Importantly, combination of JNK and ASCT2 inhibitors synergistically inhibits glutamine metabolism and tumor growth in vivo. These findings reveal a phosphorylation-palmitoylation axis linking JNK-mediated ASCT2 palmitoylation and glutamine metabolism, offering a potential therapeutic strategy for non-small cell lung cancer.