MCTR1 inhibits ferroptosis by promoting NRF2 expression to attenuate hepatic ischemia-reperfusion injury

Abstract

Hepatic ischemia-reperfusion injury (HIRI) can lead to poor prognosis in patients undergoing liver transplantation or extensive liver resection. Maresin conjugate in tissue regeneration 1 (MCTR1) exerts a protective effect in several inflammatory disease models, but its role in HIRI remains unknown. In this study, we examined the effect of MCTR1 on HIRI and its underlying mechanism. HIRI mice and oxygen-glucose deprivation/reperfusion (OGD/R) AML12 cell models were used to evaluate the effects of MCTR1 at different doses on HIRI. Histological changes, inflammatory mediators, and ferroptosis-associated markers including iron content, oxidative stress and antioxidant activity, cell death marker (LDH), and the expression of Nuclear factor erythroid-derived 2-like 2 (NRF2) were analyzed. The results showed that MCTR1 treatment significantly ameliorated liver tissue damage and AST/ALT levels in HIRI mice. It also ameliorated ferroptosis in both HIRI mice and OGD/R AML12 cells, including a decrease in iron content, serum LDH release levels, reactive oxygen species (ROS), MDA, IL-1β levels, and COX2 and transferrin receptor (TFRC) expression. In addition, it increased the levels of IL-10, the antioxidant stress markers SOD and GSH, and the expression of GPX4. With respect to the underlying mechanism, the expression of NRF2 in HIRI mice and OGD/R AML12 cells was significantly inhibited. MCTR1 treatment restored the inhibition of NRF2 expression caused by ischemia-reperfusion, and NRF2 inhibitors significantly inhibited nuclear aggregation of NRF2 promoted by MCTR1. In conclusion, the MCTR1 ameliorates ferroptosis-induced hepatic ischemia-reperfusion injury by promoting NRF2 expression and may represent a therapeutic strategy for treating HIRI.NEW & NOTEWORTHY MCTR1 exerts a protective effect in several inflammatory disease models, but its role in hepatic HIRI remains unknown. We confirm that the MCTR1 ameliorates ferroptosis-induced hepatic ischemia-reperfusion injury by promoting NRF2 expression. Our study illustrates the mechanism that MCTR1 protects from HIRI and identifies a therapeutic target for liver transplantation ischemia-reperfusion injury from the perspective of ferroptosis.

Keywords: MCTR1; Nrf2; ferroptosis; ischemia-reperfusion injury; liver.