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Dual targeting of SLC25A51 and succinate dehydrogenase selectively depletes mitochondrial NAD+ to eradicate

Ang Jia1, Xiaowen Zhang2, Ji-Hao Zhou3

  • 1Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Drug Clinical Trial Center, Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Institute of Clinical Mass Spectrometry, Shanghai Academy of Experimental Medicine, Shanghai, China; State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer, Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China.

Cell Metabolism
|January 30, 2026
PubMed

Insights

New research identifies Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations as key drivers of aggressive Acute Myeloid Leukemia (AML). A novel dual-targeting compound selectively eliminates KRAS-mutant AML cells by disrupting mitochondrial NAD+ metabolism.

Area of Science:

  • Oncology
  • Molecular Biology
  • Metabolic Pathways

Background:

  • Acute Myeloid Leukemia (AML) heterogeneity complicates treatment, with aggressive drivers often remaining unidentified.
  • Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are implicated in hyperproliferative and therapy-resistant AML, but current inhibitors show limited efficacy.

Purpose of the Study:

  • To identify novel therapeutic targets and strategies for KRAS-mutant AML.
  • To investigate the metabolic vulnerabilities associated with KRAS-driven AML.

Main Methods:

  • Utilized dual physiological/glucose-deprived screening to identify selective cytotoxic compounds.
  • Investigated the mechanism of action of compound 615, focusing on succinate dehydrogenase (SDH) and SLC25A51 inhibition.
  • Analyzed mitochondrial NAD+ metabolism and protein succinylation in KRAS-mutant versus wild-type AML cells.

Main Results:

  • Compound 615 selectively eliminates KRAS-mutant AML cells by inhibiting both SDH and the mitochondrial NAD+ transporter SLC25A51.
  • KRAS-mutant cells exhibit reduced SLC25A51 succinylation, creating a synthetic lethal vulnerability exploited by compound 615.
  • Dual inhibition leads to catastrophic mitochondrial NAD+ depletion in KRAS-mutant cells, while KRAS-wild-type cells maintain NAD+ homeostasis.

Conclusions:

  • KRAS mutations confer a specific metabolic vulnerability in AML related to mitochondrial NAD+ transport.
  • Compound 615 represents a promising dual-inhibition therapeutic strategy for KRAS-driven AML.
  • Understanding KRAS-specific metabolic dependencies opens new avenues for targeted AML therapies.
Keywords:
NAD(+)OGDH complexSLC25A51leukemiametabolism

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