复旦大学叶浩彬小组的研究发现SLC25A51和琥珀酸脱氢酶的双重靶向选择性地消耗线粒体NAD⁺以根除KRAS驱动的AML。该研究于2026年1月29日发表于国际一流学术期刊《细胞—代谢》杂志上。

该课题组发现Kirsten大鼠肉瘤病毒癌基因同源（KRAS）突变驱动超增殖和治疗/葡萄糖应激抵抗性AML，而现有抑制剂缺乏足够的细胞毒性。双重生理/葡萄糖剥夺筛选发现化合物615通过同时抑制琥珀酸脱氢酶（SDH）和细胞质-线粒体NAD⁺转运体SLC25A51选择性地消除KRAS突变细胞。在机制上，KRAS突变细胞表现出减少的2-氧戊二酸脱氢酶复合物介导的SLC25A51 K264琥珀酰化，这是一种线粒体NAD⁺依赖性修饰，促进蛋白质稳定性。

这产生了一种合成的致命脆弱性：低剂量615通过急性抑制SLC25A51触发级联失败，随后其不稳定，引导完全转运蛋白抑制。与同时发生的SDH抑制一起，这导致了线粒体NAD+的灾难性耗尽。相反，KRAS野生型细胞通过足够的基线琥珀酰-SLC25A51来保存NAD⁺内流，这稳定了SLC25A51，并使足够的琥珀酸积累驱动缺氧诱导因子1亚单位α (HIF1α)介导的代偿性NAD⁺产生。他们的工作揭示了KRAS特异性代谢易感性，并提出了KRAS驱动的AML的双重抑制疗法。

研究人员表示，急性髓性白血病（AML）由多种突变引起，但其最具侵略性的驱动因素仍然是恶性的。

附：英文原文

Title: Dual targeting of SLC25A51 and succinate dehydrogenase selectively depletes mitochondrial NAD+ to eradicate KRAS-driven AML

Author: Ang Jia, Xiaowen Zhang, Ji-Hao Zhou, Yongcan Ma, Jing Wang, Yongbo Gong, Wenjie Song, Hangcheng Hu, Yufei Yu, Haixia Yang, Youli Lu, Linzhang Huang, Xingrong Du, Chunmei Chang, Shanshan Pei, Peng Li, Craig T. Jordan, Tong-Jin Zhao, Haobin Ye

Issue&Volume: 2026-01-29

Abstract: Acute myeloid leukemia (AML) arises from diverse mutations, yet its most aggressive drivers remain elusive. Here, we show that Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations drive hyperproliferative and therapy-/glucose stress-resistant AML, whereas existing inhibitors lack sufficient cytotoxicity. Dual physiological/glucose-deprived screening identified compound 615 selectively eliminating KRAS-mutant cells through concurrently inhibiting succinate dehydrogenase (SDH) and the cytosol-to-mitochondrial NAD+ transporter SLC25A51. Mechanistically, KRAS-mutant cells exhibit reduced 2-oxoglutarate dehydrogenase complex-mediated SLC25A51 K264 succinylation, a mitochondrial NAD+-dependent modification promoting protein stability. This creates a synthetic lethal vulnerability: low-dose 615 triggers a cascade failure by acutely inhibiting SLC25A51, followed by its destabilization, causing complete transporter suppression. Together with concurrent SDH inhibition, this drives catastrophic mitochondrial NAD+ depletion. Conversely, KRAS-wild-type cells preserve NAD+ influx via sufficient baseline succinyl-SLC25A51, which stabilizes SLC25A51 and enables sufficient succinate accumulation to drive hypoxia inducible factor 1 subunit alpha (HIF1α)-mediated compensatory NAD+ production during treatment. Our work reveals a KRAS-specific metabolic vulnerability and proposes a dual-inhibition therapy for KRAS-driven AML.

DOI: 10.1016/j.cmet.2026.01.001

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(26)00001-X