Lactate dehydrogenase B noncanonically promotes ferroptosis defense in KRAS-driven lung cancer
Liang Zhao, Haibin Deng, Jingyi Zhang, Nicola Zamboni, Haitang Yang, Yanyun Gao, Yang Zhang, Duo Xu, Haiqing Zhong, Geert van Geest, Rémy Bruggmann, Qinghua Zhou, Ralph A. Schmid, Thomas M. Marti, Patrick Dorn, Ren‐Wang Peng
Abstract
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.