2. Academic Validation
  3. Regorafenib inhibits EphA2 phosphorylation and leads to liver damage via the ERK/MDM2/p53 axis

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

  • Nat Commun. 2023 May 13;14(1):2756. doi: 10.1038/s41467-023-38430-8.
Hao Yan 1,  Wentong Wu 1,  Yuhuai Hu 2 3,  Jinjin Li 1,  Jiangxin Xu 1,  Xueqin Chen 4 5,  Zhifei Xu 1,  Xiaochun Yang 1,  Bo Yang 6,  Qiaojun He 1 2,  Peihua Luo 7 8 9
Affiliations

Affiliations

  • 1 Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • 2 Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, 310018, China.
  • 3 Laboratory of Fruit Quality Biology/Zhejiang Provincial Key Laboratory of Horticultural Plant Integrative Biology/The State Agriculture Ministry Laboratory of Horticultural Plant Growth, Development and Quality Improvement, Zhejiang University, Hangzhou, 310058, China.
  • 4 Department of Oncology, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou, 310002, China.
  • 5 Cancer Center, Zhejiang University, Hangzhou, 310058, China.
  • 6 Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • 7 Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. peihualuo@zju.edu.cn.
  • 8 Department of Pharmacology and Toxicology, Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310018, China. peihualuo@zju.edu.cn.
  • 9 Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Hangzhou, 310002, China. peihualuo@zju.edu.cn.
PMID: 37179400 DOI: 10.1038/s41467-023-38430-8
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.

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