Investigating the role of ferroptosis in the pathogenesis of murine models of metabolic dysfunction-associated steatohepatitis (MASH)

Abstract Non-alcoholic steatohepatitis (NASH) is a chronic liver disease that develops from simple fatty liver and progresses to hepatitis, liver fibrosis, cirrhosis, and eventually liver cancer, in the absence of significant alcohol consumption. Recently, the term NASH has been replaced with metabolic dysfunction-associated steatohepatitis (MASH) on the basis of new diagnostic criteria. Cell death may lead to damage associated molecular patterns (DAMPs)-mediated inflammatory response and is therefore considered a key therapeutic target in chronic liver diseases. However, the impact of cell death on the long-term pathogenesis of MASH remains uncertain. We have reported that ferroptosis precedes apoptosis in lipid-accumulating hepatocytes, followed by hepatitis in a murine model of NASH. Because lipid peroxidation is an essential step in ferroptosis, glutathione peroxidase 4 (GPX4), which reduces phospholipid hydroperoxides, plays a crucial role in ferroptosis inhibition. However, the role of GPX4 in MASH remains unclear. Here, we investigated the role of ferroptosis in the pathogenesis of MASH by promoting or inhibiting ferroptosis in murine models of MASH. To promote ferroptosis, we generated liver-specific Gpx4 knockout ( Gpx4 LKO) mice and fed them two distinct MASH diets. Although lipid peroxidation tended to increase in Gpx4 LKO mouse liver compared with control mouse liver, no significant difference in liver fibrosis was noted between the two mouse groups, suggesting that enhancing ferroptosis had a limited influence on the pathology of MASH. In contrast, inhibiting ferroptosis by vitamin E administration reduced lipid peroxidation, ameliorating liver fibrosis. These results suggest that inhibiting ferroptosis is a promising therapeutic target in the long-term pathogenesis of MASH, whereas enhancing ferroptosis has a limited impact on liver fibrosis.