Regorafenib inhibits EphA2 phosphorylation damages the liver via ERK/MDM2/p53 axis

Abstract

Abstract Hepatotoxicity of regorafenib is one of the most noteworthy concerns for patients, however the mechanism has poorly understood. Hence, lack of effective intervention strategy. In this study, we found that regorafenib-induced liver injury mainly derived from its non-therapeutic target EPH receptor A2 (EphA2) by comparing the target with sorafenib. EphA2 deficiency attenuated liver damage and cell apoptosis under regorafenib treatment. Overexpression of EphA2-S898A could directly cause hepatocyte apoptosis, while recovering EphA2 Ser898 phosphorylation greatly alleviated regorafenib-induced liver injury. Mechanistically, regorafenib inhibits EphA2 Ser897 phosphorylation and reduced ubiquitination of p53 by altering the intracellular localization of mouse double minute 2 (MDM2) through affecting the extracellular signal-regulated kinase (ERK)/MDM2 axis. Meanwhile, we found Schisandrin C which could upregulate the phosphorylation of EphA2 at Ser897 also had 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 on EphA2 Ser897 represents a potential therapeutic strategy to prevent regorafenib-induced hepatotoxicity.