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The integral membrane protein smim4 modulates redox balance via malate compartmentalization in pancreatic cancer

Author

Listed:
  • Bo Wang

    (Wenzhou Medical University)

  • Xinyu Han

    (Zhangzhou Affiliated Hospital of Fujian Medical University
    Wenzhou Medical University)

  • Xianlong Lin

    (Wenzhou Medical University)

  • Jinjing Wang

    (Wenzhou Medical University)

  • Chang You

    (Wenzhou Medical University)

  • Keke Chen

    (Wenzhou Medical University)

  • Yu Chen

    (Wenzhou Medical University)

  • Fanhao Meng

    (Wenzhou Medical University)

  • Huihui Jiang

    (Wenzhou Medical University)

  • Fulong Zheng

    (Wenzhou Medical University)

  • Yiqing Zhang

    (Wenzhou Medical University)

  • Jinya Lyu

    (Wenzhou Medical University)

  • Yuxiao Bai

    (The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University)

  • Xiaoning Qu

    (The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University)

  • Danyi Zhou

    (Wenzhou Medical University)

  • Minghua Jiang

    (The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University)

  • Wei Cui

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Jianxin Lyu

    (Wenzhou Medical University
    Hangzhou Medical College)

  • Hezhi Fang

    (Wenzhou Medical University
    Chinese Academy of Medical Sciences and Peking Union Medical College
    Wenzhou Medical University)

Abstract

Reshaping metabolic compartmentalization is frequently observed in cancer cells, however, the underlying mechanisms and physiological implications are less known. Here, we show that pancreatic ductal adenocarcinoma (PDAC) patients with low integral membrane protein SMIM4 expression exhibits a poor prognosis and reduces oxidative stress in tumors, which can be confirmed in cultured human PDAC cells and mice Pdx1-Cre/KrasG12D/+/Trp53R172H/+ (KPC) cells. Mechanistically, SMIM4 interacts with and facilitates the assembly of SLC25A1-containing complexes, enabling SLC25A1-mediated malate/citrate exchange. Depleting SMIM4 has little effect on mitochondrial respiration but impairs the assembly of SLC25A1-containing complexes, thereby reshaping of malate compartmentalization. This shift promotes NADPH generation through increased cytosolic conversion of malate to pyruvate, protecting cells from glucose deprivation-induced apoptosis. Moreover, PDAC cells with low level of SMIM4 are resistant to RSL3-induced toxicity, indicating that PDAC tumors with high SMIM4 expression are promising candidates for treatment with oxidative stress inducers.

Suggested Citation

  • Bo Wang & Xinyu Han & Xianlong Lin & Jinjing Wang & Chang You & Keke Chen & Yu Chen & Fanhao Meng & Huihui Jiang & Fulong Zheng & Yiqing Zhang & Jinya Lyu & Yuxiao Bai & Xiaoning Qu & Danyi Zhou & Min, 2025. "The integral membrane protein smim4 modulates redox balance via malate compartmentalization in pancreatic cancer," Nature Communications, Nature, vol. 16(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64734-y
    DOI: 10.1038/s41467-025-64734-y
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