Inhibition of eEF2 kinase ameliorates hepatic injury induced by ACR through regulation of the MAPK pathway.

Background And Aims: Acrylamide (ACR) induces hepatotoxicity, yet its underlying mechanisms remain incompletely understood. Our prior proteomic analysis of serum from occupationally ACR-exposed individuals identified significantly elevated levels of eukaryotic elongation factor 2 (eEF2). Given that eEF2 activity is regulated by its phosphorylation status, which is solely mediated by eukaryotic elongation factor 2 kinase (eEF2K), we investigated the role of eEF2K in ACR-induced hepatic injury.

Methods: eEF2K gene knockout (eEF2K) mice were used to assess the impact of eEF2K ablation on ACR-induced hepatotoxicity. Downstream mechanisms were explored by liver metabolomics and Western blot analysis.

Results: ACR exposure significantly increased hepatic eEF2K expression and eEF2 phosphorylation (P < 0.05). eEF2K knockout (KO) significantly attenuated ACR-induced hepatic injury, indicated by improved histopathology, reduced serum ALT/AST levels, and restored liver coefficients (P < 0.05). Metabolomics revealed that eEF2K ablation counteracted ACR-induced perturbations in sphingolipid metabolism. Mechanistically, eEF2K deficiency normalized sphingolipid metabolism and prevented MAPK signaling dysregulation induced by ACR.

Conclusions: This study identifies eEF2K as a key regulator in ACR-induced hepatic injury. ACR exposure promotes MAPK signaling hyperactivation via eEF2K-dependent dysregulation of sphingolipid metabolism, contributing to hepatic injury. Inhibition of eEF2K attenuates ACR-induced hepatic injury. Inhibition of eEF2K represents a novel therapeutic strategy for mitigating ACR-associated hepatic injury.