Targeting Jun N-terminal kinase phosphorylation: A human-derived hepatoprotective peptide human liver transplantation peptide 1 attenuates hepatic ischemia-reperfusion injury

BACKGROUND Hepatic ischemia-reperfusion injury (HIRI) is a major complication in liver transplantation with limited treatment options. Peptidomics offers a promising approach to discover therapeutic peptides. AIM To identify novel peptides from human liver transplants that could mitigate HIRI and preliminarily explore their mechanisms. METHODS Liver samples from six transplant patients were analyzed using nano-liquid chromatography-tandem mass spectrometry. A candidate peptide, human liver transplantation peptide 1 (HLTP1), was screened in a murine HIRI model and validated in vitro using AML12 cells. Mechanisms were probed via Jun N-terminal kinase (JNK) phosphorylation analysis and rescue experiments with a JNK activator. RESULTS HLTP1 was identified as a protective peptide. It reduced liver damage and apoptosis in mice, enhanced cell viability and proliferation, and decreased apoptosis in AML12 cells. Mechanistically, HLTP1 inhibited JNK phosphorylation, and its effects were reversed by JNK activation. CONCLUSION HLTP1 alleviates HIRI by inhibiting JNK-mediated apoptosis, representing a potential therapeutic strategy for liver transplantation.