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Peer-reviewedCC BY 4.0Clinical and Translational Medicine

Selective AUTAC‐mediated ATP7B degradation unlocks cuproptosis vulnerability in pancreatic ductal adenocarcinoma

  • Zihan Zhang1
  • Min Li1
  • Jiale Feng2
  • Jian‐Ang Li2
  • Lei Zhang2
  1. 1Department of Interventional Radiology Zhongshan Hospital Fudan University Shanghai China
  2. 2Department of Pancreatic Surgery Zhongshan Hospital Fudan University Shanghai China
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Abstract

Cuproptosis arises from mitochondrial copper overload, yet how tumour cells evade this metabolic vulnerability remains unclear. We identify ATP7B as the central barrier to cuproptosis in pancreatic ductal adenocarcinoma (PDAC). ATP7B is aberrantly upregulated in PDAC and predicts poor prognosis. Its depletion increases intracellular copper, activates FDX1, DLAT/DLST lipoylation, disrupts tricarboxylic acid (TCA) metabolism, and reinstates cuproptosis in vitro and in vivo. Mechanistically, ATP7B undergoes ZBTB10‐driven K63‐linked ubiquitination, recognized by NBR1 for selective autophagic degradation. Leveraging this, we developed an ATP7B‐targeting autophagy‐targeting chimera (ATAUTAC) that promotes ATP7B clearance, amplifies copper‐driven mitochondrial metabolic perturbations, triggers cuproptosis, and inhibits tumour growth with favourable tolerability. Notably, ATAUTAC sensitizes PDAC to gemcitabine, overcoming resistance by exposing latent metabolic fragility. These findings establish ATP7B as a mechanistic hub of cuproptosis tolerance and demonstrate that autophagy‐based ATP7B degradation is a druggable strategy for copper‐dependent tumour eradication. ATAUTAC offers a promising avenue for precision therapy in PDAC and other refractory malignancies.

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Cite

BibTeXRIS
BibTeX
@article{zhang2026selective,
  title = {{Selective AUTAC‐mediated ATP7B degradation unlocks cuproptosis vulnerability in pancreatic ductal adenocarcinoma}},
  author = {Zihan Zhang and Min Li and Jiale Feng and Jian‐Ang Li and Lei Zhang},
  journal = {Clinical and Translational Medicine},
  year = {2026},
  month = oct,
  doi = {10.1002/ctm2.70848},
  url = {https://doi.org/10.1002/ctm2.70848},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Selective AUTAC‐mediated ATP7B degradation unlocks cuproptosis vulnerability in pancreatic ductal adenocarcinoma
AU  - Zihan Zhang
AU  - Min Li
AU  - Jiale Feng
AU  - Jian‐Ang Li
AU  - Lei Zhang
PY  - 2026
DA  - 2026/10/27
JO  - Clinical and Translational Medicine
DO  - 10.1002/ctm2.70848
UR  - https://doi.org/10.1002/ctm2.70848
AB  - Cuproptosis arises from mitochondrial copper overload, yet how tumour cells evade this metabolic vulnerability remains unclear. We identify ATP7B as the central barrier to cuproptosis in pancreatic ductal adenocarcinoma (PDAC). ATP7B is aberrantly upregulated in PDAC and predicts poor prognosis. Its depletion increases intracellular copper, activates FDX1, DLAT/DLST lipoylation, disrupts tricarboxylic acid (TCA) metabolism, and reinstates cuproptosis in vitro and in vivo. Mechanistically, ATP7B undergoes ZBTB10‐driven K63‐linked ubiquitination, recognized by NBR1 for selective autophagic degradation. Leveraging this, we developed an ATP7B‐targeting autophagy‐targeting chimera (ATAUTAC) that promotes ATP7B clearance, amplifies copper‐driven mitochondrial metabolic perturbations, triggers cuproptosis, and inhibits tumour growth with favourable tolerability. Notably, ATAUTAC sensitizes PDAC to gemcitabine, overcoming resistance by exposing latent metabolic fragility. These findings establish ATP7B as a mechanistic hub of cuproptosis tolerance and demonstrate that autophagy‐based ATP7B degradation is a druggable strategy for copper‐dependent tumour eradication. ATAUTAC offers a promising avenue for precision therapy in PDAC and other refractory malignancies.
SN  - 2001-1326
ER  -