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Lactate dehydrogenase B noncanonically promotes ferroptosis defense in KRAS-driven lung cancer
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Lactate dehydrogenase B noncanonically promotes ferroptosis defense in KRAS-driven lung cancer
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Journal Article
Lactate dehydrogenase B noncanonically promotes ferroptosis defense in KRAS-driven lung cancer
2025
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/31
/ 13/51
/ 13/89
/ 14/34
/ 38/77
/ 42/44
/ 82/80
/ 96/109
/ 96/63
/ Animals
/ Biomedical and Life Sciences
/ Defense
/ Humans
/ L-Lactate Dehydrogenase - genetics
/ L-Lactate Dehydrogenase - metabolism
/ Lipids
/ Mice
/ Proto-Oncogene Proteins p21(ras) - genetics
/ Proto-Oncogene Proteins p21(ras) - metabolism
