Activity-Dependent Effects of ERK1/2 on Hepatic Ischemia-Reperfusion Injury

  • Transplant Proc. 2025 Aug 11:S0041-1345(25)00350-1. doi: 10.1016/j.transproceed.2025.07.005.
Joohyun Kim  1 ,  Seung-Keun Hong  2 ,  Alice Lee  3 ,  Suresh N Kumar  4 ,  Mariko Suchi  4 ,  Jong-In Park  5
Affiliations
  • 1. Department of Surgery, Yale University School of Medicine, New Haven, CT. Electronic address: [email protected].
  • 2. Department of Anesthesia, Medical College of Wisconsin, Milwaukee, WI.
  • 3. Department of Surgery, Medical College of Wisconsin, Milwaukee, WI.
  • 4. Department of Pathology, Medical College of Wisconsin, Milwaukee, WI.
  • 5. Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI.
PMID: 40796392 DOI: 10.1016/j.transproceed.2025.07.005
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.

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