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Lactate dehydrogenase B noncanonically promotes ferroptosis defense in KRAS-driven lung cancer

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机构： [1]Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland. [2]Department for BioMedical Research (DBMR), University of Bern, Bern,Switzerland. [3]Second Department of Thoracic Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University,Changsha, Hunan 410013, China. [4]Department of Biology, Institute of Molecular Systems Biology, Swiss Federal Institute of Technology/ETH Zürich, Zurich, Switzerland. [5]PHRTSwiss Multi-Omics Center, smoc.ethz.ch, Zurich, Switzerland. [6]Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China. [7]LungCancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, China. [8]Department of Thoracic Surgery, Fujian Medical University Union Hospital,Fuzhou City, Fujian, China. [9]Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. [10]Interfaculty Bioinformatics Unit and SwissInstitute of Bioinformatics, University of Bern, Bern, Switzerland. [11]Present address: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI48109, USA.

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Ferroptosis is an oxidative, non-apoptotic cell death frequently inactivated in cancer, but the underlying mechanisms in oncogene-specific tumors remain poorly understood. Here, we discover that lactate dehydrogenase (LDH) B, but not the closely related LDHA, subunits of active LDH with a known function in glycolysis, noncanonically promotes ferroptosis defense in KRAS-driven lung cancer. Using murine models and human-derived tumor cell lines, we show that LDHB silencing impairs glutathione (GSH) levels and sensitizes cancer cells to blockade of either GSH biosynthesis or utilization by unleashing KRAS-specific, ferroptosis-catalyzed metabolic synthetic lethality, culminating in increased glutamine metabolism, oxidative phosphorylation (OXPHOS) and mitochondrial reactive oxygen species (mitoROS). We further show that LDHB suppression upregulates STAT1, a negative regulator of SLC7A11, thereby reducing SLC7A11-dependent GSH metabolism. Our study uncovers a previously undefined mechanism of ferroptosis resistance involving LDH isoenzymes and provides a novel rationale for exploiting oncogene-specific ferroptosis susceptibility to treat KRAS-driven lung cancer.© 2024. The Author(s).

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大类 | 1 区

生物学

小类 | 1 区生化与分子生物学 2 区细胞生物学

第一作者：

第一作者机构： [1]Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland. [2]Department for BioMedical Research (DBMR), University of Bern, Bern,Switzerland. [11]Present address: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI48109, USA.

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通讯机构： [1]Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland. [2]Department for BioMedical Research (DBMR), University of Bern, Bern,Switzerland.

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