Mitochondrial Calcium Uniporter Drives Chemoresistance in Pancreatic Cancer via Glutathione-Mediated Stemness Maintenance

Zekun Li; Chenyang Meng; Guangcong Shen; Yueying Shan; Junjin Wang; Diliyaer Abudukeremu; Rui Zhao; Bo Ni; Chao Xu; Xiaofan Guo; Jun Yu; Kaiyuan Wang; Shengyu Yang; Yun Zhan Li; Yongjie Xie; Tianxing Zhou; Jihui Hao; Xiuchao Wang

doi:10.1002/advs.202507346

Mitochondrial Calcium Uniporter Drives Chemoresistance in Pancreatic Cancer via Glutathione-Mediated Stemness Maintenance

Zekun Li
, Chenyang Meng
, Guangcong Shen
, Yueying Shan
, Junjin Wang
, Diliyaer Abudukeremu
, Rui Zhao
, Bo Ni
, Chao Xu
, Xiaofan Guo
, Jun Yu
, Kaiyuan Wang
, Shengyu Yang
, Yun Zhan Li
, Yongjie Xie
, Tianxing Zhou
, Jihui Hao
, Xiuchao Wang

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy with poor prognosis due to chemoresistance. Using integrative single-cell RNA sequencing, we identified that the upregulation of mitochondrial calcium uniporter (MCU) may contribute to chemoresistance and stemness maintenance in PDAC. MCU was highly expressed in chemotherapy-resistant PDAC tumors and correlated with enhanced cancer stem cell properties. Mechanistically, MCU-mediated mitochondrial Ca²⁺ influx triggered endoplasmic reticulum (ER) stress and the downstream PERK-eIF2α pathway. This cascade activated ATF4 and NRF2, which enhanced the transcriptional regulation of PSAT1 and SLC7A11. These changes promoted de novo glutathione (GSH) synthesis to scavenge reactive oxygen species (ROS) and sustain stemness. Genetic knockdown or pharmacological inhibition of MCU disrupted GSH synthesis, suppressed stemness, and restored sensitivity to nab-paclitaxel plus gemcitabine (AG). High-throughput screening identified MCU inhibitor NB-598, which synergized with AG to inhibit tumor growth in preclinical models. These findings offer a potential novel therapeutic strategy to address chemoresistance in PDAC.

Original language	English (US)
Article number	e07346
Journal	Advanced Science
Volume	13
Issue number	17
DOIs	https://doi.org/10.1002/advs.202507346
State	Published - Mar 23 2026

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

All Science Journal Classification (ASJC) codes

Medicine (miscellaneous)
General Chemical Engineering
Biochemistry, Genetics and Molecular Biology (miscellaneous)
General Materials Science
General Engineering
General Physics and Astronomy

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10.1002/advs.202507346

Cite this

Li, Z., Meng, C., Shen, G., Shan, Y., Wang, J., Abudukeremu, D., Zhao, R., Ni, B., Xu, C., Guo, X., Yu, J., Wang, K., Yang, S., Li, Y. Z., Xie, Y., Zhou, T., Hao, J., & Wang, X. (2026). Mitochondrial Calcium Uniporter Drives Chemoresistance in Pancreatic Cancer via Glutathione-Mediated Stemness Maintenance. Advanced Science, 13(17), Article e07346. https://doi.org/10.1002/advs.202507346

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title = "Mitochondrial Calcium Uniporter Drives Chemoresistance in Pancreatic Cancer via Glutathione-Mediated Stemness Maintenance",

abstract = "Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy with poor prognosis due to chemoresistance. Using integrative single-cell RNA sequencing, we identified that the upregulation of mitochondrial calcium uniporter (MCU) may contribute to chemoresistance and stemness maintenance in PDAC. MCU was highly expressed in chemotherapy-resistant PDAC tumors and correlated with enhanced cancer stem cell properties. Mechanistically, MCU-mediated mitochondrial Ca2+ influx triggered endoplasmic reticulum (ER) stress and the downstream PERK-eIF2α pathway. This cascade activated ATF4 and NRF2, which enhanced the transcriptional regulation of PSAT1 and SLC7A11. These changes promoted de novo glutathione (GSH) synthesis to scavenge reactive oxygen species (ROS) and sustain stemness. Genetic knockdown or pharmacological inhibition of MCU disrupted GSH synthesis, suppressed stemness, and restored sensitivity to nab-paclitaxel plus gemcitabine (AG). High-throughput screening identified MCU inhibitor NB-598, which synergized with AG to inhibit tumor growth in preclinical models. These findings offer a potential novel therapeutic strategy to address chemoresistance in PDAC.",

author = "Zekun Li and Chenyang Meng and Guangcong Shen and Yueying Shan and Junjin Wang and Diliyaer Abudukeremu and Rui Zhao and Bo Ni and Chao Xu and Xiaofan Guo and Jun Yu and Kaiyuan Wang and Shengyu Yang and Li, \{Yun Zhan\} and Yongjie Xie and Tianxing Zhou and Jihui Hao and Xiuchao Wang",

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doi = "10.1002/advs.202507346",

language = "English (US)",

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AU - Li, Zekun

AU - Meng, Chenyang

AU - Shen, Guangcong

AU - Shan, Yueying

AU - Wang, Junjin

AU - Abudukeremu, Diliyaer

AU - Zhao, Rui

AU - Ni, Bo

AU - Xu, Chao

AU - Guo, Xiaofan

AU - Yu, Jun

AU - Wang, Kaiyuan

AU - Yang, Shengyu

AU - Li, Yun Zhan

AU - Xie, Yongjie

AU - Zhou, Tianxing

AU - Hao, Jihui

AU - Wang, Xiuchao

PY - 2026/3/23

Y1 - 2026/3/23

N2 - Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy with poor prognosis due to chemoresistance. Using integrative single-cell RNA sequencing, we identified that the upregulation of mitochondrial calcium uniporter (MCU) may contribute to chemoresistance and stemness maintenance in PDAC. MCU was highly expressed in chemotherapy-resistant PDAC tumors and correlated with enhanced cancer stem cell properties. Mechanistically, MCU-mediated mitochondrial Ca2+ influx triggered endoplasmic reticulum (ER) stress and the downstream PERK-eIF2α pathway. This cascade activated ATF4 and NRF2, which enhanced the transcriptional regulation of PSAT1 and SLC7A11. These changes promoted de novo glutathione (GSH) synthesis to scavenge reactive oxygen species (ROS) and sustain stemness. Genetic knockdown or pharmacological inhibition of MCU disrupted GSH synthesis, suppressed stemness, and restored sensitivity to nab-paclitaxel plus gemcitabine (AG). High-throughput screening identified MCU inhibitor NB-598, which synergized with AG to inhibit tumor growth in preclinical models. These findings offer a potential novel therapeutic strategy to address chemoresistance in PDAC.

AB - Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy with poor prognosis due to chemoresistance. Using integrative single-cell RNA sequencing, we identified that the upregulation of mitochondrial calcium uniporter (MCU) may contribute to chemoresistance and stemness maintenance in PDAC. MCU was highly expressed in chemotherapy-resistant PDAC tumors and correlated with enhanced cancer stem cell properties. Mechanistically, MCU-mediated mitochondrial Ca2+ influx triggered endoplasmic reticulum (ER) stress and the downstream PERK-eIF2α pathway. This cascade activated ATF4 and NRF2, which enhanced the transcriptional regulation of PSAT1 and SLC7A11. These changes promoted de novo glutathione (GSH) synthesis to scavenge reactive oxygen species (ROS) and sustain stemness. Genetic knockdown or pharmacological inhibition of MCU disrupted GSH synthesis, suppressed stemness, and restored sensitivity to nab-paclitaxel plus gemcitabine (AG). High-throughput screening identified MCU inhibitor NB-598, which synergized with AG to inhibit tumor growth in preclinical models. These findings offer a potential novel therapeutic strategy to address chemoresistance in PDAC.

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UR - https://www.scopus.com/pages/publications/105028095039#tab=citedBy

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ER -

Mitochondrial Calcium Uniporter Drives Chemoresistance in Pancreatic Cancer via Glutathione-Mediated Stemness Maintenance

Abstract

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