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

Ferroptosis is an oxidative, non-apoptotic form of cell death that is frequently inactivated in cancer, yet its regulation in oncogene-specific tumors remains poorly understood. Here, we identify lactate dehydrogenase B (LDHB)—but not the closely related LDHA—as a noncanonical regulator of ferroptosis defense in KRAS-driven lung cancer. Using murine models and human-derived tumor cell lines, we demonstrate that LDHB silencing impairs glutathione (GSH) levels, sensitizing cancer cells to inhibitors of either GSH biosynthesis or utilization. This triggers a KRAS-specific ferroptosis-driven synthetic lethality, characterized by increased glutamine metabolism, oxidative phosphorylation (OXPHOS), and mitochondrial reactive oxygen species (mitoROS). Furthermore, we show that LDHB suppression upregulates STAT1, a negative regulator of SLC7A11, thereby reducing SLC7A11-dependent GSH metabolism. Our findings reveal a previously unrecognized role of LDH isoenzymes in ferroptosis resistance and provide a novel therapeutic rationale for targeting oncogene-specific ferroptosis susceptibility in KRAS-driven lung cancer.

Prof. Ren-Wang Peng is a cancer researcher specializing in translational oncology and therapeutic resistance. He earned his Ph.D. from the Chinese Academy of Sciences and has conducted research at the Max Planck Institute and ETH Zürich. His work focuses on lung cancer and mesothelioma, with an emphasis on cancer stem cells and drug resistance mechanisms. Prof. Peng has published extensively in leading scientific journals and collaborates internationally on cancer research initiatives. He is currently an Associate Professor and Lab Head at the University Hospital of Bern (Inselspital) and a faculty member at the University of Bern’s Faculty of Medicine.