Abstract

Ferroptosis, a form of non-apoptotic cell death program driven by excessive lipid peroxidation and an important mechanism of tumor suppression, is frequently dysregulated in cancer. However, the mechanisms underlying impaired ferroptosis in oncogene-specific tumors remain poorly understood. Here we report a non- canonical role of lactate dehydrogenase B (LDHB), whose main activity is the conversion of lactate to pyruvate, in protecting KRAS-mutated lung cancer from ferroptosis. Silencing of LDHB impairs intracellular glutathione (GSH) metabolism and drives the hypersensitivity of KRAS-mutant cells to ferroptosis inducers by inhibiting the SLC7A11/GSH/GPX4 axis, a central antioxidant system against lipid peroxidation and ferroptosis by catalyzing GSH synthesis and utilization. Mechanistically, LDHB promotes SLC7A11 expression and GSH biosynthesis, and inhibition of LDHB confers metabolic synthetic lethality with ferroptosis inducers due to increased glutaminolysis and production of reactive oxygen species (ROS) in mitochondria, ultimately triggering ferroptosis of KRAS-driven lung cancer cells. Consequently, combined inhibition of LDHB and SLC7A11 synergistically suppresses tumor growth in multiple KRAS-mutant lung cancer implants and in an autochthonous model of Kras-induced lung adenocarcinoma. Taken together, our results reveal a hitherto unrecognized mechanism of ferroptosis defense by glycolytic LDHB and suggest a new strategy for the treatment of KRAS-dependent lung cancer.