RAMP1 Protects Hepatocytes against Ischemia-reperfusion Injury by Inhibiting the ERK/YAP Pathway

Background and Aims: Hepatic ischemia-reperfusion injuReceived: 27 July 2023 | Revised: 3 January 2024 | Accepted: 2 February 2024 | Published online: 29 February, 2024-ry (HIRI) is a prevalent complication of liver transplantation, partial hepatectomy, and severe infection, necessitating the development of more effective clinical strategies. Receptor activity-modifying protein 1 (RAMP1), a member of the G protein-coupled receptor adapter family, has been implicated in numerous physiological and pathological processes. The study aims to investigate the pathogenesis of RAMP1 in HIRI. Methods: We established a 70% liver ischemia-reperfusion model in RAMP1 knockout (KO) and wild-type mice. Liver and blood samples were collected after 0, 6, and 24 h of hy-poxia/reperfusion. Liver histological and serological analyses were performed to evaluate liver damage. We also conduct-ed in-vitro and in-vivo experiments to explore the molecular mechanism underlying RAMP1 function. Results: Liver injury was exacerbated in RAMP1-KO mice compared with the sham group, as evidenced by increased cell death and elevated serum transaminase and inflammation levels. HIRI was pro-moted in RAMP1-KO mice via the induction of hepatocyte ap optosis and inhibition of proliferation. The absence of RAMP1 led to increased activation of the extracellular signal-regu-lated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway and yes-associated protein (YAP) phosphorylation, ultimately promoting apoptosis. SCH772984, an ERK/MAPK phosphorylation inhibitor, and PY-60, a YAP phosphorylation inhibitor, reduced apoptosis in in-vitro and in-vivo experi-ments. Conclusions: Our findings suggest that RAMP1 pro-tects against HIRI by inhibiting ERK and YAP phosphorylation signal transduction, highlighting its potential as a therapeutic target for HIRI and providing a new avenue for intervention