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

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, Minghua Jiang (), Wei Cui (), Jianxin Lyu () and Hezhi Fang ()
Additional contact information
Bo Wang: Wenzhou Medical University
Xinyu Han: Zhangzhou Affiliated Hospital of Fujian 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
Hezhi Fang: Wenzhou Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-64734-y

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