The integral membrane protein smim4 modulates redox balance via malate compartmentalization in pancreatic cancer
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/Kras<sup>G12D/+</sup>/Trp53R<sup>172H/+</sup> (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.
Authors
- Danyi Zhou
- Xianlong Lin
- Hezhi Fang (ORCID: https://orcid.org/0000-0003-0956-3160)
- Keke Chen (ORCID: https://orcid.org/0009-0000-6214-1392)
- Xiaoning Qu
- Fuyuan Zheng (ORCID: https://orcid.org/0000-0003-0485-2422)
- Junfang Lyu (ORCID: https://orcid.org/0009-0006-0259-2427)
- Jianxin Lyu (ORCID: https://orcid.org/0000-0003-2343-1666)
- Bo Wang (ORCID: https://orcid.org/0000-0002-6047-1221)
- Yang Bai (ORCID: https://orcid.org/0000-0003-2652-7022)
- Yu Chen (ORCID: https://orcid.org/0000-0001-9651-9875)
- Wei Cui (ORCID: https://orcid.org/0000-0002-0947-5091)
- Jinjing Wang (ORCID: https://orcid.org/0000-0002-3777-745X)
- Xinyu Han (ORCID: https://orcid.org/0009-0002-0831-6774)
- Yiqing Zhang (ORCID: https://orcid.org/0000-0003-4434-6890)
- Chang You (ORCID: https://orcid.org/0009-0009-4676-7905)
- Minghua Jiang (ORCID: https://orcid.org/0000-0003-0606-2547)
- Huihui Jiang (ORCID: https://orcid.org/0000-0002-5046-305X)
- Fan‐hao Meng
Institutions
- Fujian Medical University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Wenzhou Medical University (CN)
- National Cancer Center (US)
- Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University (CN)
- Zhangzhou Municipal Hospital of Fujian Province (CN)
- Zhejiang Provincial People's Hospital (CN)
- Hangzhou Medical College (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-05
- DOI
- https://doi.org/10.1038/s41467-025-64734-y
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Wenzhou Medical University
- National Natural Science Foundation of China
- Chinese Academy of Medical Sciences
- Young Scientists Fund
- Natural Science Foundation of Zhejiang Province