Faculty Collaboration Database

Activity-Dependent Effects of ERK1/2 on Hepatic Ischemia-Reperfusion Injury. Transplant Proc 2025 Oct;57(8):1659-1667

Date

08/13/2025

Pubmed ID

40796392

DOI

10.1016/j.transproceed.2025.07.005

Scopus ID

2-s2.0-105013138459 (requires institutional sign-in at Scopus site)   1 Citation

Abstract

BACKGROUND: Liver transplantation remains the only cure for end-stage liver disease, but ischemia-reperfusion injury (IRI) limits graft availability. Although extracellular signal-regulated kinase (ERK1/2) signaling is involved in cellular responses to IRI, its precise role in hepatic IRI remains unclear. We investigated the role of ERK1/2 in hepatic IRI by modulating its activity using small-molecule chemical inhibitors.

METHODS: ERK1/2 activation was monitored at different phases of hepatic IRI using a rat model in which liver ischemia was induced with varying reperfusion times. ERK1/2 activity was modulated in this model by administering different doses of trametinib (MEK1/2 inhibitor) and BCI (DUSP1/6 inhibitor). Liver injury was evaluated through histological assessment, serum markers, and molecular analysis of cell death pathways.

RESULTS: ERK1/2 activity increased early in the reperfusion phase and gradually decreased over 6 hours thereafter. Inhibiting the ERK1/2 activity increase using trametinib (0.3 mg/kg) as well as inhibiting its decreases using BCI (7.5 mg/kg) worsened the liver injury. However, the injury was reduced upon titrating ERK1/2 activity to a moderately increased level by BCI and trametinib coadministration. The reduced liver injury was accompanied by decreased expression of ferroptosis markers.

CONCLUSIONS: Our data demonstrate that ERK1/2 activity is required for hepatic cells to tolerate IRI. Our results suggest that modulation of ERK1/2 activity using existing drugs may be a potential therapeutic strategy for mitigating hepatic IRI.

Author List

Kim J, Hong SK, Lee A, Kumar SN, Suchi M, Park JI

Authors

Suresh Kumar PhD Associate Professor in the Pathology and Laboratory Medicine department at Medical College of Wisconsin
Jong-In Park PhD Professor in the Biochemistry department at Medical College of Wisconsin
Mariko Suchi PhD, MD Professor in the Pathology and Laboratory Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Disease Models, Animal
Liver
Liver Transplantation
MAP Kinase Signaling System
Male
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Protein Kinase Inhibitors
Pyridones
Pyrimidinones
Rats
Rats, Sprague-Dawley
Reperfusion Injury