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

  • Cell Discov. 2026 Feb 24;12(1):13. doi: 10.1038/s41421-026-00870-z.
Xingyu Chen  #  1 ,  Zihao Ke  #  1 ,  Shihui Wei  #  1 ,  Jiajin Chen  1 ,  Ke Zhu  1 ,  Jiaqi Xu  1 ,  Yun Zhao  1 ,  Mengyuan Cen  1 ,  Yan Jin  1 ,  Zhilei Pan  1 ,  Juan Xiong  1 ,  Ying Chen  2 ,  Chenfang Dong  3 ,  Qianhua Cao  4 ,  Chao Cao  5
Affiliations
  • 1. Key Laboratory of Respiratory Disease of Ningbo, Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China.
  • 2. Institute of Engineering Medicine, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China.
  • 3. Department of Pathology and Pathophysiology, and Department of Surgical Oncology (breast center), Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. [email protected].
  • 4. Key Laboratory of Respiratory Disease of Ningbo, Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China. [email protected].
  • 5. Key Laboratory of Respiratory Disease of Ningbo, Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China. [email protected].
  • # Contributed equally.
PMID: 41730846 DOI: 10.1038/s41421-026-00870-z
Abstract

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.

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