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EMP1 safeguards hematopoietic stem cells by suppressing sphingolipid metabolism and alleviating endoplasmic reticulum stress

Lei Li, Yufei Lei, Yan Li, Yuxin Xie, Pusheng Hui, Xiaoyan Zang, Weiru Wu, Feng Wu, Jiankun Fan, Jianming Wang, Jieping Chen (), Zhe Chen () and Yu Hou ()
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Lei Li: Chongqing University
Yufei Lei: Chongqing Medical University
Yan Li: Third Military Medical University (Army Medical University)
Yuxin Xie: Chongqing Medical University
Pusheng Hui: The First Affiliated Hospital of Chongqing Medical University
Xiaoyan Zang: The First Affiliated Hospital of Chongqing Medical University
Weiru Wu: Third Military Medical University (Army Medical University)
Feng Wu: Chongqing Medical University
Jiankun Fan: Chongqing Medical University
Jianming Wang: Chongqing Medical University
Jieping Chen: Chongqing University
Zhe Chen: Chongqing Medical University
Yu Hou: Chongqing Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract The long-term maintenance of hematopoietic stem cells (HSCs) relies on the regulation of endoplasmic reticulum (ER) stress at a low level, but the underlying mechanism remains poorly understood. Here, we demonstrate that suppression of ER stress improves the functions of HSCs and protects HSCs against ionizing radiation (IR)-induced injury. We identify epithelial membrane protein 1 (EMP1) as a key regulator that mitigates ER stress in HSCs. Emp1 deficiency leads to the accumulation of protein aggregates and elevated ER stress, ultimately resulting in impaired HSC maintenance and self-renewal. Mechanistically, EMP1 is located within the ER and interacts with ceramide synthase 2 (CERS2) to limit the production of a class of sphingolipids, dihydroceramides (dhCers). DhCers accumulate in Emp1-deficient HSCs and induce protein aggregation. Furthermore, Emp1 deficiency renders HSCs more susceptible to IR, while overexpression of Emp1 or inhibition of CERS2 protects HSCs against IR-induced injury. These findings highlight the critical role played by the EMP1-CERS2-dhCers axis in constraining ER stress and preserving HSC potential.

Date: 2025
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DOI: 10.1038/s41467-025-61552-0

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