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USP3 stabilizes MIC19 by deubiquitination under hypoxic stress and promotes the progression of non-small cell lung cancer

Acta Pharmacologica Sinica (2025)Cite this article

Abstract

Hypoxia is a common phenomenon in the microenvironment of solid tumors; mitochondria, as the site of cellular oxidative respiration, are among the first organelles to be affected under hypoxic conditions. Mitochondrial cristae organizing protein 19 (MIC19), a core component of the mitochondrial contact site and cristae organizing system (MICOS), is essential for preserving mitochondrial activity. In this study, we investigated the effects of hypoxia on MIC19 and its regulatory mechanisms in non-small cell lung cancer (NSCLC). We showed that the expression levels of MIC19 were significantly increased in NSCLC, which were associated with advanced stages and a poor prognosis in patients with NSCLC. We demonstrated that MIC19 promoted the proliferation and invasion of A549 and PC9 cells in vitro, and MIC19 played a crucial role in maintaining mitochondrial function. We revealed that USP3 mediated the hypoxia-induced upregulation of MIC19 expression in A549 and PC9 cells. In the hypoxic microenvironment, HIF-1α bound to the USP3 promoter region and promoted USP3 expression, which in turn stabilized MIC19 through K48-linked deubiquitination, thereby driving NSCLC progression. The role of MIC19 in NSCLC growth and progression was confirmed in nude mice bearing A549 xenograft tumors in vivo. In conclusion, under hypoxic conditions, USP3 stabilizes MIC19 through deubiquitination, thereby promoting NSCLC progression. This study reveals the HIF1α–USP3–MIC19 axis in NSCLC progression, providing a theoretical basis for future therapeutic strategies.

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Fig. 1: MIC19 plays an important role in NSCLC progression.
Fig. 2: MIC19 maintains mitochondrial structure and function and promotes NSCLC progression via ROS.
Fig. 3: MIC19 is stabilized through deubiquitination under hypoxic stress.
Fig. 4: USP3 mediates the hypoxia-induced increase in MIC19 expression.
Fig. 5: USP3 directly interacts with MIC19 and regulates its protein stability.
Fig. 6: USP3 deubiquitinates MIC19.
Fig. 7: USP3 promotes NSCLC progression through MIC19.
Fig. 8: Schematic diagram illustrating hypoxia-induced promotion of USP3 transcription by HIF-1α, leading to MIC19 stabilization through deubiquitination and subsequent NSCLC progression.

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Supplementary information is available at the website of Acta Pharmacologica Sinica.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (82473191, 82072595, and 82172569). Natural Science Foundation of Tianjin (23JCZDJC00710, 23JCYBJC01010). Tianjin Health Science and Technology Project (TJWJ2022XK005). Beijing Science and Technology Innovation Medical Development Fund grant (KC2023-JX-0288-PZ78).

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  1. These authors contributed equally: Wen-hao Zhao, Hua Huang, Chen Ding

Authors and Affiliations

  1. Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, 300052, China

    Wen-hao Zhao, Hua Huang, Chen Ding, Ze-xia Zhao, Chao-yi Jia, Ying-jie Wang, Zi-xuan Hu, Guan-nan Wang, Jing-hao Liu & Jun Chen

  2. Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China

    Yong-wen Li, Hong-yu Liu & Jun Chen

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Contributions

JC, WHZ, and HYL designed the research studies. WHZ, CD, HH, ZXZ, CYJ, YJW, ZXH, and GNW performed the experiments. YWL, HH, CD, and ZXZ analyzed data. WHZ, HH and JHL wrote the manuscript. JC provided financial support. HYL, YWL, and JHL supervised the project.

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Correspondence to Hong-yu Liu or Jun Chen.

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Zhao, Wh., Huang, H., Ding, C. et al. USP3 stabilizes MIC19 by deubiquitination under hypoxic stress and promotes the progression of non-small cell lung cancer. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01625-4

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