Integrated Single-Cell and Transcriptomic Analysis Suggests a Cuproptosis-Related Phenotype and Potential Therapeutic Target in Acute Pancreatitis
- 1The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
- 2Institute of Animal Nutrition and Feed Sciences, College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
Abstract
Acute pancreatitis (AP) is an acute inflammatory disorder of the exocrine pancreas with limited therapies. Whether cuproptosis, a copper-dependent cell death pathway, contributes to AP pathogenesis remains unknown. We integrated single-cell transcriptomics (GSE279876), single-cell transcriptomics (GSE188819), and human whole-blood transcriptomic data (GSE194331) to evaluate 13 cuproptosis-related genes across cell types, along with pseudotime trajectory, regulatory networks, and cell–cell communication. Findings were validated in caerulein-induced severe acute pancreatitis (SAP) mouse models and acinar cell injury using histopathology, electron microscopy, flow cytometry, immunofluorescence, and biochemical assays. Single-cell analysis showed selective activation of a cuproptosis-related signature in acinar cells, with all 13 genes upregulated, most notably GIs and Fdx1. The cuproptosis-related gene signature score increased along with pseudotime, and exploratory transcription factor (TF) and cell–cell communication analyses suggested enrichment of SPI1 and AP-1 (FOS/JUN), alongside MIF/CCL inflammatory signals, which was corroborated in independent datasets. In vitro and in vivo, pancreatic tissues and pancreatic acinar cells in SAP exhibited copper accumulation, FDX1/DLAT upregulation, mitochondrial shrinkage, and cristae loss, which are consistent with a cuproptosis-related phenotype, and were all attenuated by Tetrathiomolybdate (TTM). These findings suggest that the inflammatory microenvironment may be associated with selective activation of a cuproptosis-related program in acinar cells in AP, and that copper chelation with TTM attenuates pancreatic injury, indicating a potential therapeutic strategy targeting copper dyshomeostasis.
Related
- 124 Integrated single-cell transcriptomic profiling of urine-derived cells as a strategy for non-invasive therapeutic monitoring in bladder cancer
- An AI-integrated pharmacophore and transcriptomic framework for rapid discovery of therapeutic leads for ischemic stroke
- Cuproptosis in glioma: mechanisms, biological roles and therapeutic perspectives
- Ferroptosis and Cuproptosis in the Pathogenesis of Breast Cancer: Molecular Mechanisms, Crosstalk, and Therapeutic Perspectives
- Integrative transcriptomic analysis of peripheral blood identifies NETosis-associated programs and a stratified adaptive immune suppression pattern in severe acute pancreatitis
BibTeX
@article{xie2026integrated,
title = {{Integrated Single-Cell and Transcriptomic Analysis Suggests a Cuproptosis-Related Phenotype and Potential Therapeutic Target in Acute Pancreatitis}},
author = {Qingfeng Xie and Maoqin He and Qi Wang and Weiqin Li},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27209004},
url = {https://www.mdpi.com/1422-0067/27/20/9004},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Integrated Single-Cell and Transcriptomic Analysis Suggests a Cuproptosis-Related Phenotype and Potential Therapeutic Target in Acute Pancreatitis
AU - Qingfeng Xie
AU - Maoqin He
AU - Qi Wang
AU - Weiqin Li
PY - 2026
DA - 2026/10/01
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27209004
UR - https://www.mdpi.com/1422-0067/27/20/9004
AB - Acute pancreatitis (AP) is an acute inflammatory disorder of the exocrine pancreas with limited therapies. Whether cuproptosis, a copper-dependent cell death pathway, contributes to AP pathogenesis remains unknown. We integrated single-cell transcriptomics (GSE279876), single-cell transcriptomics (GSE188819), and human whole-blood transcriptomic data (GSE194331) to evaluate 13 cuproptosis-related genes across cell types, along with pseudotime trajectory, regulatory networks, and cell–cell communication. Findings were validated in caerulein-induced severe acute pancreatitis (SAP) mouse models and acinar cell injury using histopathology, electron microscopy, flow cytometry, immunofluorescence, and biochemical assays. Single-cell analysis showed selective activation of a cuproptosis-related signature in acinar cells, with all 13 genes upregulated, most notably GIs and Fdx1. The cuproptosis-related gene signature score increased along with pseudotime, and exploratory transcription factor (TF) and cell–cell communication analyses suggested enrichment of SPI1 and AP-1 (FOS/JUN), alongside MIF/CCL inflammatory signals, which was corroborated in independent datasets. In vitro and in vivo, pancreatic tissues and pancreatic acinar cells in SAP exhibited copper accumulation, FDX1/DLAT upregulation, mitochondrial shrinkage, and cristae loss, which are consistent with a cuproptosis-related phenotype, and were all attenuated by Tetrathiomolybdate (TTM). These findings suggest that the inflammatory microenvironment may be associated with selective activation of a cuproptosis-related program in acinar cells in AP, and that copper chelation with TTM attenuates pancreatic injury, indicating a potential therapeutic strategy targeting copper dyshomeostasis.
SN - 1422-0067
ER -