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Peer-reviewedCC BYILIVER

Single-cell profiling reveals GABBR1 as a cuproptosis-regulated prognostic biomarker in pancreatic cancer.

  • Jie Gong1,2,3,4
  • Weinan Zhang1,5
  • Li Tang3,4
  • Yuxi Long1,6
  • Xianxing Wang3,4
  • Jiali Yang3,4
  • Yongjun Yang3,4
  • Roberto Montalti7
  • Roberto Ivan Troisi7
  • Huaizhi Wang1,3,4
7 affiliations
  1. 1University of Chinese Academy of Sciences (UCAS) Chongqing School, Chongqing Medical University, Chongqing 400016, China.
  2. 2Chongqing School, University of Chinese Academy of Sciences, Chongqing 400714, China.
  3. 3Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing 401147, China.
  4. 4Chongqing General Hospital, Key Laboratory of Intelligent Medicine Engineering for Hepatopancreatobiliary Diseases, Chongqing 401147, China.
  5. 5Center of Urology and Nephrology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 401336, China.
  6. 6Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, Chongqing University, Chongqing 401147, China.
  7. 7Department of Clinical Medicine and Surgery, Federico II University Hospital, Naples 80131, Italy.
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Abstract

Cuproptosis is a recently identified copper-dependent form of cell death with potential therapeutic applications. However, its activity in cancer-associated fibroblasts (CAFs) and its association with pancreatic cancer (PC) prognosis remain poorly understood. This study aimed to address this gap. We performed integrated analyses of scRNA-seq data from patients with PC (GSE212966) and The Cancer Genome Atlas-pancreatic adenocarcinoma dataset. Based on cuproptosis-related AUCell scores, fibroblasts were stratified into high-score (cuproptosis-high) and low-score (cuproptosis-low) groups. Weighted gene coexpression network analysis (WGCNA) was used to identify modules associated with cuproptosis-related genes (CRGs), followed by random survival forest modeling to screen prognostic genes. Functional assessments included gene set variation analysis, immune infiltration analysis via CIBERSORT, and immunohistochemistry for experimental validation. scRNA-seq analysis identified fibroblasts as the principal cell type with elevated cuproptosis activity. By integrating WGCNA with survival analysis, we identified GABBR1 as a key gene whose expression decreased with increase in tumor progression. Fibroblasts expressing higher GABBR1 levels also exhibited increased expression of immune checkpoint genes and T-cell activation markers. A nomogram integrating GABBR1 expression with clinical features showed strong prognostic performance. Immunohistochemical validation confirmed that GABBR1, LIAS, and LIPT1 were expressed at significantly lower levels in tumor tissues than in adjacent normal tissues. Importantly, GABBR1 expression negatively correlated with PC progression and was linked to CRGs (LIAS and LIPT1), emerging as a novel CAF-specific biomarker. Modulating GABBR1 can reshape cuproptosis pathways, thereby influencing apoptotic sensitivity and modulating immune responses.

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Cite

BibTeXRIS
BibTeX
@article{gong2026singlecell,
  title = {{Single-cell profiling reveals GABBR1 as a cuproptosis-regulated prognostic biomarker in pancreatic cancer.}},
  author = {Jie Gong and Weinan Zhang and Li Tang and Yuxi Long and Xianxing Wang and Jiali Yang and Yongjun Yang and Roberto Montalti and Roberto Ivan Troisi and Huaizhi Wang},
  journal = {ILIVER},
  year = {2026},
  month = oct,
  doi = {10.1016/j.iliver.2026.100276},
  url = {https://europepmc.org/article/MED/42999371},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Single-cell profiling reveals GABBR1 as a cuproptosis-regulated prognostic biomarker in pancreatic cancer.
AU  - Jie Gong
AU  - Weinan Zhang
AU  - Li Tang
AU  - Yuxi Long
AU  - Xianxing Wang
AU  - Jiali Yang
AU  - Yongjun Yang
AU  - Roberto Montalti
AU  - Roberto Ivan Troisi
AU  - Huaizhi Wang
PY  - 2026
DA  - 2026/10/15
JO  - ILIVER
DO  - 10.1016/j.iliver.2026.100276
UR  - https://europepmc.org/article/MED/42999371
AB  - Cuproptosis is a recently identified copper-dependent form of cell death with potential therapeutic applications. However, its activity in cancer-associated fibroblasts (CAFs) and its association with pancreatic cancer (PC) prognosis remain poorly understood. This study aimed to address this gap. We performed integrated analyses of scRNA-seq data from patients with PC (GSE212966) and The Cancer Genome Atlas-pancreatic adenocarcinoma dataset. Based on cuproptosis-related AUCell scores, fibroblasts were stratified into high-score (cuproptosis-high) and low-score (cuproptosis-low) groups. Weighted gene coexpression network analysis (WGCNA) was used to identify modules associated with cuproptosis-related genes (CRGs), followed by random survival forest modeling to screen prognostic genes. Functional assessments included gene set variation analysis, immune infiltration analysis via CIBERSORT, and immunohistochemistry for experimental validation. scRNA-seq analysis identified fibroblasts as the principal cell type with elevated cuproptosis activity. By integrating WGCNA with survival analysis, we identified GABBR1 as a key gene whose expression decreased with increase in tumor progression. Fibroblasts expressing higher GABBR1 levels also exhibited increased expression of immune checkpoint genes and T-cell activation markers. A nomogram integrating GABBR1 expression with clinical features showed strong prognostic performance. Immunohistochemical validation confirmed that GABBR1, LIAS, and LIPT1 were expressed at significantly lower levels in tumor tissues than in adjacent normal tissues. Importantly, GABBR1 expression negatively correlated with PC progression and was linked to CRGs (LIAS and LIPT1), emerging as a novel CAF-specific biomarker. Modulating GABBR1 can reshape cuproptosis pathways, thereby influencing apoptotic sensitivity and modulating immune responses.
SN  - 2772-9478
ER  -