Zhao Liang, Deng Haibin, Zhang Jingyi, Zamboni Nicola, Yang Haitang, Gao Yanyun, Yang Zhang, Xu Duo, Zhong Haiqing, van Geest Geert, Bruggmann Rémy, Zhou Qinghua, Schmid Ralph A, Marti Thomas M, Dorn Patrick, Peng Ren-Wang
Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland.
Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland.
Cell Death Differ. 2025 Apr;32(4):632-645. doi: 10.1038/s41418-024-01427-x. Epub 2024 Dec 7.
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.
铁死亡是一种氧化性的、非凋亡性的细胞死亡，在癌症中常常失活，但在致癌基因特异性肿瘤中的潜在机制仍知之甚少。在此，我们发现乳酸脱氢酶（LDH）B而非密切相关的LDHA（在糖酵解中具有已知功能的活性LDH亚基）非经典地促进KRAS驱动的肺癌中的铁死亡防御。利用小鼠模型和人源肿瘤细胞系，我们表明沉默LDHB会损害谷胱甘肽（GSH）水平，并通过释放KRAS特异性的、铁死亡催化的代谢合成致死性，使癌细胞对GSH生物合成或利用的阻断敏感，最终导致谷氨酰胺代谢、氧化磷酸化（OXPHOS）和线粒体活性氧（mitoROS）增加。我们进一步表明，抑制LDHB会上调SLC7A11的负调节因子STAT1，从而减少SLC7A11依赖性的GSH代谢。我们的研究揭示了一种以前未定义的涉及LDH同工酶的铁死亡抗性机制，并为利用致癌基因特异性铁死亡易感性治疗KRAS驱动的肺癌提供了新的理论依据。
