Related Experiment Video

Updated: Jul 30, 2025

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
07:49

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

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

Hao Yan1, Wentong Wu1, Yuhuai Hu2,3

  • 1Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.

Nature Communications
|May 13, 2023
PubMed

Insights

Regorafenib causes liver injury by inhibiting Eph receptor A2 (EphA2) phosphorylation. Activating EphA2 phosphorylation offers a potential strategy to prevent this regorafenib-induced hepatotoxicity.

Area of Science:

  • Hepatology
  • Molecular Toxicology
  • Oncology Pharmacology

Background:

  • Regorafenib hepatotoxicity is a significant clinical concern with an unclear mechanism.
  • Understanding regorafenib's molecular targets is crucial for developing effective interventions.

Purpose of the Study:

  • To elucidate the mechanism of regorafenib-induced liver injury.
  • To identify therapeutic targets for mitigating regorafenib hepatotoxicity.

Main Methods:

  • Comparative target analysis of regorafenib and sorafenib.
  • Investigated the role of Eph receptor A2 (EphA2) in regorafenib-induced liver injury using a mouse model.
  • Examined the effects of regorafenib on EphA2 phosphorylation, p53 ubiquitination, and the ERK/MDM2 pathway.
  • Evaluated the protective effect of schisandrin C against regorafenib toxicity.

Main Results:

  • Regorafenib-induced liver injury is primarily mediated by its non-therapeutic target, EphA2.
  • EphA2 deficiency significantly reduced liver damage and apoptosis in mice treated with regorafenib.
  • Regorafenib inhibits EphA2 Ser897 phosphorylation, impacting p53 ubiquitination via the ERK/MDM2 axis.
  • Schisandrin C demonstrated a protective effect against regorafenib hepatotoxicity in vivo.

Conclusions:

  • Inhibition of EphA2 Ser897 phosphorylation is a key mechanism underlying regorafenib-induced hepatotoxicity.
  • Chemical activation of EphA2 Ser897 phosphorylation presents a promising therapeutic strategy for preventing regorafenib-induced liver injury.

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