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SP600125, a selective JNK inhibitor, is a potent inhibitor of NAD(P)H: quinone oxidoreductase 1 (NQO1)

Acta Pharmacologica Sinica volume 46, pages 1137–1144 (2025)Cite this article

Abstract

The c-Jun N-terminal kinases (JNKs) has been identified as a critical modulator in multiple cellular processes, including stress stimulus, inflammation, cell proliferation, apoptosis, etc. SP600125 is a widely used ATP-competitive reversible JNKs inhibitor. NAD(P)H: quinone oxidoreductase 1 (NQO1) is a flavoprotein mediated two or four electron-reduction of quinones. Here, we showed that SP600125 bind to the active pocket of NQO1 and inhibit NQO1 activity. SP600125 exhibits comparable inhibitory effects on NQO1-mediated quinone bioactivation, H2O2 generation, and cell death, as the specific NQO1 inhibitor dicoumarol (DIC). Importantly, the inhibitory effects of SP600125 on NQO1 are independent of JNKs inhibition. These results suggested that SP600125 is a novel NQO1 inhibitor, which provides new insights into the mechanism of action of SP600125. Furthermore, SP600125 should be used more cautiously as a JNKs inhibitor, especially when NQO1 is highly expressed.

SP600125 competed with β-Lap (NQO1-bioactivated drugs) for binding to NQO1, and inhibited NQO1-dependent cell death.

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Fig. 1: SP600125 binds and inhibits NQO1.
Fig. 2: SP600125 inhibits β-lap-induced ROS and H2O2 generation.
Fig. 3: SP600125 reverses β-Lap-induced cell membrane rupture and cell death.
Fig. 4: SP600125 inhibits NQO1 independent of JNK1/2 inhibition.
Fig. 5: SP600125 inhibits NQO1 in vivo.

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Acknowledgements

This work was supported by the Science and Technology Development Fund of Macau SAR (0070/2022/A2, 0081/2021/A2), the Research Fund of University of Macau (MYRG-GRG2023-00072-ICMS-UMDF), and the Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau (SP2023-00001-FSCPO).

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Authors and Affiliations

  1. State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China

    Bing-ling Zhong, Yi-fei Zhang, Hao-yi Zheng & Xiu-ping Chen

  2. Faculty of Health Sciences, University of Macau, Macao, China

    Qiang Chen & Xiu-ping Chen

  3. MoE Frontiers Science Center for Precision Oncology, University of Macau, Macao, China

    Qiang Chen & Xiu-ping Chen

  4. Department of Pathology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen Clinical Research Center for Cancer Therapy, Xiamen, 361015, China

    Hua-dong Lu

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  1. Bing-ling Zhong
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  3. Hao-yi Zheng
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BLZ and XPC designed the research; BLZ, YFZ, and HYZ performed the research; BLZ analyzed the data; BLZ, XPC, QC and HDL wrote and reviewed the paper.

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Correspondence to Hua-dong Lu or Xiu-ping Chen.

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Zhong, Bl., Zhang, Yf., Zheng, Hy. et al. SP600125, a selective JNK inhibitor, is a potent inhibitor of NAD(P)H: quinone oxidoreductase 1 (NQO1). Acta Pharmacol Sin 46, 1137–1144 (2025). https://doi.org/10.1038/s41401-024-01418-1

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