Inhibition of EphA2 phosphorylation leads to liver damage via the ERK/ MDM2/p53 axis

Inhibition of EphA2 phosphorylation leads to liver damage

Peihua Luo

2.7

Drug-induced liver injury (DILI) refers to unintended hepatic damage resulting from pharmacological interventions. DILI manifests primarily through hepatocellular injury and cholestasis, wherein hepatocellular injury is predominantly mediated by regulated modes of cell death. Potential mechanisms include oxidative stress, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and DNA damage. However, universal molecular targets underlying hepatocyte toxicity remain elusive. Among hepatotoxic agents, small molecule kinase inhibitors (SMKIs) constitute a distinct class. Unlike conventional cytotoxic chemotherapy, SMKIs demonstrate targeted anti-neoplastic efficacy with reduced systemic adverse effects. Nevertheless, SMKIs are associated with unique toxicities, notably hepatotoxicity. For instance, regorafenib, a second-line therapy for hepatocellular carcinoma, received FDA black box warnings for severe hepatotoxicity upon market release. Based on prior evidence, a specific adverse outcome pathway (AOP) has been identified, potentially mediated by Eph receptor A2 (EphA2), a regorafenib off-target. This AOP may elucidate molecular mechanisms driving hepatotoxicity. In this AOP, the Molecular Initiating Event (MIE) is "Inhibition of EphA2 phosphorylation (Ser 897)," triggering four Key Events (KEs): "Decrease p-ERK," " Decrease p-MDM2," "Decrease the degradation of p53" and "Hepatocyte apoptosis," Ultimately, this pathway culminates in the Adverse Outcome (AO) of Liver injury.

<div> <table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>Influence or Outcome</th> <th>KER(s) involved</th> </tr> </thead> <tbody> <tr> <td> </td> <td> </td> <td> </td> </tr> </tbody> </table> </div>

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