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Regorafenib inhibits EphA2 phosphorylation and leads to liver damage via the ERK/MDM2/p53 axis

Author

Listed:
  • Hao Yan

    (Zhejiang University)

  • Wentong Wu

    (Zhejiang University)

  • Yuhuai Hu

    (Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University
    Development and Quality Improvement, Zhejiang University)

  • Jinjin Li

    (Zhejiang University)

  • Jiangxin Xu

    (Zhejiang University)

  • Xueqin Chen

    (Zhejiang University School of Medicine, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province
    Cancer Center, Zhejiang University)

  • Zhifei Xu

    (Zhejiang University)

  • Xiaochun Yang

    (Zhejiang University)

  • Bo Yang

    (Zhejiang University)

  • Qiaojun He

    (Zhejiang University
    Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University)

  • Peihua Luo

    (Zhejiang University
    Zhejiang University
    Zhejiang University School of Medicine)

Abstract

The hepatotoxicity of regorafenib is one of the most noteworthy concerns for patients, however the mechanism is poorly understood. Hence, there is a lack of effective intervention strategies. Here, by comparing the target with sorafenib, we show that regorafenib-induced liver injury is mainly due to its nontherapeutic target Eph receptor A2 (EphA2). EphA2 deficiency attenuated liver damage and cell apoptosis under regorafenib treatment in male mice. Mechanistically, regorafenib inhibits EphA2 Ser897 phosphorylation and reduces ubiquitination of p53 by altering the intracellular localization of mouse double minute 2 (MDM2) by affecting the extracellular signal-regulated kinase (ERK)/MDM2 axis. Meanwhile, we found that schisandrin C, which can upregulate the phosphorylation of EphA2 at Ser897 also has protective effect against the toxicity in vivo. Collectively, our findings identify the inhibition of EphA2 Ser897 phosphorylation as a key cause of regorafenib-induced hepatotoxicity, and chemical activation of EphA2 Ser897 represents a potential therapeutic strategy to prevent regorafenib-induced hepatotoxicity.

Suggested Citation

  • Hao Yan & Wentong Wu & Yuhuai Hu & Jinjin Li & Jiangxin Xu & Xueqin Chen & Zhifei Xu & Xiaochun Yang & Bo Yang & Qiaojun He & Peihua Luo, 2023. "Regorafenib inhibits EphA2 phosphorylation and leads to liver damage via the ERK/MDM2/p53 axis," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38430-8
    DOI: 10.1038/s41467-023-38430-8
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    References listed on IDEAS

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    1. Ygal Haupt & Ruth Maya & Anat Kazaz & Moshe Oren, 1997. "Mdm2 promotes the rapid degradation of p53," Nature, Nature, vol. 387(6630), pages 296-299, May.
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