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

## TL;DR

This paper shows how a protein modification pathway involving JNK1 and ZDHHC14 controls glutamine transport and cancer progression, offering new treatment ideas for lung cancer.

## Contribution

The study identifies a novel phosphorylation-palmitoylation axis linking JNK1 to ASCT2 regulation and glutamine metabolism in NSCLC.

## Key findings

- ZDHHC14 palmitoylates ASCT2 at Cys39 and Cys48, promoting its lysosomal degradation.
- JNK1 phosphorylates ZDHHC14 at Thr440, reducing ASCT2 degradation and stabilizing glutamine transport.
- Combining JNK and ASCT2 inhibitors synergistically inhibits tumor growth in vivo.

## 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.