非小细胞肺癌（NSCLC）是最致命和最常见的恶性肿瘤之一。 LKB1/STK11 肿瘤抑制基因在约 30% 的 NSCLC 中发生突变，通常是肺腺癌 (LUAD)。我们将斑马鱼和人肺类器官作为协同平台，以临床前筛选选择性针对 LKB1 缺陷肿瘤的代谢化合物。有趣的是，两种激酶抑制剂，白皮杉醇和酪氨酸磷酸化蛋白 23，似乎通过 LKB1 突变发挥合成致死作用。虽然LKB1的损失本身会加速能量消耗，但我们意外地发现它还改变了关键的能量稳态维持因子瘦素（LEP）的调节，进一步增加了能量负担并暴露了一个脆弱点；对所识别的化合物获得敏感性。我们发现，复合治疗通过拮抗 Von Hippel-Lindau (VHL) 介导的 HIF1A 泛素化来稳定缺氧诱导因子 1-α (HIF1A)，从而驱动 LEP 过度激活。重要的是，我们证明，在已经受到攻击的 LKB1 缺陷细胞中，对白皮杉酚/酪氨酸磷酸化蛋白 23 的敏感性上位依赖于 HIF1A-LEP 解偶联蛋白 2 (UCP2) 信号轴，降低细胞能量以维持生存。因此，我们发现了 LKB1 缺陷型肿瘤的关键代谢脆弱性，可以使用我们确定的化合物作为线粒体解偶联剂来治疗性利用这一脆弱性。© 2024。作者。

Non-small cell lung cancer (NSCLC) constitutes one of the deadliest and most common malignancies. The LKB1/STK11 tumour suppressor is mutated in ∼ 30% of NSCLCs, typically lung adenocarcinomas (LUAD). We implemented zebrafish and human lung organoids as synergistic platforms to pre-clinically screen for metabolic compounds selectively targeting LKB1-deficient tumours. Interestingly, two kinase inhibitors, Piceatannol and Tyrphostin 23, appeared to exert synthetic lethality with LKB1 mutations. Although LKB1 loss alone accelerates energy expenditure, unexpectedly we find that it additionally alters regulation of the key energy homeostasis maintenance player leptin (LEP), further increasing the energetic burden and exposing a vulnerable point; acquired sensitivity to the identified compounds. We show that compound treatment stabilises Hypoxia-inducible factor 1-alpha (HIF1A) by antagonising Von Hippel-Lindau (VHL)-mediated HIF1A ubiquitination, driving LEP hyperactivation. Importantly, we demonstrate that sensitivity to piceatannol/tyrphostin 23 epistatically relies on a HIF1A-LEP-Uncoupling Protein 2 (UCP2) signaling axis lowering cellular energy beyond survival, in already challenged LKB1-deficient cells. Thus, we uncover a pivotal metabolic vulnerability of LKB1-deficient tumours, which may be therapeutically exploited using our identified compounds as mitochondrial uncouplers.© 2024. The Author(s).