Zhao, LiangLiangZhaoDeng, HaibinHaibinDengZhang, JingyiJingyiZhangZamboni, NicolaNicolaZamboniYang, HaitangHaitangYang0000-0002-8732-5910Gao, YanyunYanyunGaoZhang, YangYangZhangXu, DuoDuoXuZhong, HaiqingHaiqingZhongvan Geest, GeertGeertvan GeestBruggmann, RémyRémyBruggmannZhou, QinghuaQinghuaZhouSchmid, Ralph A.Ralph A.SchmidMarti, Thomas M.Thomas M.Marti0000-0003-3005-220XDorn, PatrickPatrickDornPeng, Ren-WangRen-WangPeng2024-12-242024-12-242025-04https://boris-portal.unibe.ch/handle/20.500.12422/194561Ferroptosis 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.en600 - Technology::610 - Medicine & healtharticle10.48620/787233964371210.1038/s41418-024-01427-x