CST1 Regulates ER-Mitochondrial Mg²⁺ Balance via MAGT1 to Promote Breast Cancer Metabolism and Growth.
8 affiliations
- 1Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China.
- 2Kunming College of Life Sciences, University of Chinese Academy of Sciences, Kunming, 650204, Yunnan, China.
- 3Yunnan Key Laboratory of Breast Cancer Precision Medicine, School of Biomedical Engineering, Kunming Medical University, Kunming, 650500, China.
- 4Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
- 5Yunnan Key Laboratory of Breast Cancer Precision Medicine, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Peking University Cancer Hospital, Kunming, 650118, China.
- 6Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China.
- 7Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- 8Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Abstract
Breast cancer remains a clinical challenge and requires novel molecular targets. Here, we identify the Cystatin SN (CST1) as a critical oncoprotein upregulated in breast cancer, where its expression correlates with poor prognosis. Functionally, CST1 promotes breast cancer cell proliferation and tumor growth in vitro and in vivo, independent of its secretion. Mechanistically, CST1 physically interacts with the magnesium transporter MAGT1 on the endoplasmic reticulum (ER) membrane, and this interaction potentiates MAGT1-mediated Mg²⁺ transport, elevating mitochondrial Mg²⁺ levels and fueling mitochondrial metabolism. We developed a cell-penetrating peptide TAT-TM4₂ which disrupts the CST1-MAGT1 interface and effectively suppresses Mg²⁺ flux, mitochondrial metabolism, and tumor growth in vivo. Our study unveils a non-canonical role for a secreted protein in regulating inter-organelle ion homeostasis to drive cancer metabolism and growth, and proposes a targeted peptide-based strategy for treating breast cancer.
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BibTeX
@article{gan2026cst1,
title = {{CST1 Regulates ER-Mitochondrial Mg²⁺ Balance via MAGT1 to Promote Breast Cancer Metabolism and Growth.}},
author = {Wenqiang Gan and Min Zheng and Li Liu and Jingwen Liao and Yu Zhu and Xiaochen Hou and Qunshan Liu and Hui Li and Jing Yao and Dewei Jiang and Ceshi Chen},
journal = {International journal of biological sciences},
year = {2026},
month = sep,
doi = {10.7150/ijbs.136015},
url = {https://europepmc.org/article/MED/42910209},
note = {CC BY},
}
RIS
TY - JOUR
TI - CST1 Regulates ER-Mitochondrial Mg²⁺ Balance via MAGT1 to Promote Breast Cancer Metabolism and Growth.
AU - Wenqiang Gan
AU - Min Zheng
AU - Li Liu
AU - Jingwen Liao
AU - Yu Zhu
AU - Xiaochen Hou
AU - Qunshan Liu
AU - Hui Li
AU - Jing Yao
AU - Dewei Jiang
AU - Ceshi Chen
PY - 2026
DA - 2026/09/11
JO - International journal of biological sciences
DO - 10.7150/ijbs.136015
UR - https://europepmc.org/article/MED/42910209
AB - Breast cancer remains a clinical challenge and requires novel molecular targets. Here, we identify the Cystatin SN (CST1) as a critical oncoprotein upregulated in breast cancer, where its expression correlates with poor prognosis. Functionally, CST1 promotes breast cancer cell proliferation and tumor growth in vitro and in vivo, independent of its secretion. Mechanistically, CST1 physically interacts with the magnesium transporter MAGT1 on the endoplasmic reticulum (ER) membrane, and this interaction potentiates MAGT1-mediated Mg²⁺ transport, elevating mitochondrial Mg²⁺ levels and fueling mitochondrial metabolism. We developed a cell-penetrating peptide TAT-TM4₂ which disrupts the CST1-MAGT1 interface and effectively suppresses Mg²⁺ flux, mitochondrial metabolism, and tumor growth in vivo. Our study unveils a non-canonical role for a secreted protein in regulating inter-organelle ion homeostasis to drive cancer metabolism and growth, and proposes a targeted peptide-based strategy for treating breast cancer.
SN - 1449-2288
ER -