A non-canonical function of LDHB promotes SLC7A11-mediated glutathione metabolism and protects against glutaminolysis-dependent ferroptosis inKRAS-driven lung cancer

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.

A hybrid machine learning framework for functional annotation applied to mitochondrial glutathione metabolism and transport in cancers.

“…Agreeing with the high probability annotation for the GSH metabolic process term by our models, PC has been suggested to link glucose and GSH synthesis, along with protecting against oxidative stress and maintaining redox metabolism 73 . Recently, pyruvate metabolism has been closely linked to GSH metabolism and ferroptosis in lung cancer cells through the plasma membrane cysteine transporter SLC7A11 74 (ranked 3rd by GSH metabolic process GO term annotation probability in RF classifiers ( Supp. Data )).…”

“…PC links glucose to GSH synthesis and plays roles in the control of redox and oxidative stress 75 . Recently, pyruvate metabolism has been associated with GSH metabolism and ferroptosis in lung cancer cells through the plasma membrane cysteine transporter SLC7A11 76 (ranked 3 rd by GSH metabolic process GO term annotation probability in RF classifiers. PC is reported to specifically localize to the mitochondrial matrix with little evidence supporting it being membrane-bound; thus, it may be that PC interacts with the IMM-bound transporters to facilitate and modulate mGSH transport.…”