P2X7 receptor contributes to hepatic inflammation and collagen deposition in methionine- and choline-deficient diet-fed mice

Introduction Metabolic-Dysfunction-Associated Steatohepatitis (MASH) is characterized by hepatic steatosis, inflammation, and progressive liver injury, with growing evidence implicating purinergic signaling and inflammasome activation in disease progression. Here, we investigated the role of the P2X7 receptor and caspase-1/11 signaling in methionine- and choline-deficient (MCD) diet-induced liver injury in mice. Methods Mice were fed an MCD diet to induce liver injury, and hepatic steatosis, inflammation, and tissue injury were assessed by histopathological analysis. Hepatic triacylglycerol and cholesterol accumulation, Il1b mRNA expression, and IL-1β protein levels were evaluated. The hepatic expression profile of purinergic receptors, including P2Y 1 , P2Y 4 , P2Y 6 , P2Y 12 , and P2Y 14 , was also investigated in wild-type and P2X7- and/or caspase-1/11-deficient mice. Results MCD diet feeding induced significant weight loss and marked histopathological alterations, including hepatic steatosis, inflammatory infiltrates, and hepatocellular injury, accompanied by increased hepatic triacylglycerol and cholesterol accumulation. Hepatic injury was partially dependent on caspase-1/11 signaling, whereas hepatic inflammation was partially dependent on the P2X7 receptor. Although Il1b mRNA expression increased following MCD diet feeding, this increase was significant only in wild-type mice, whereas increased IL-1β protein levels were observed only in wild-type animals, suggesting that P2X7 receptor signaling and caspase-1/11 may contribute to IL-1β maturation during MCD diet-induced liver injury. In addition, MCD diet feeding promoted marked remodeling of the hepatic purinergic profile, characterized by downregulation of P2Y 1 and P2Y 4 receptors and genotype-dependent regulation of P2Y 12 , whereas P2Y 6 and P2Y 14 expression remained largely unchanged. Discussion Together, these findings demonstrate that the P2X7 receptor and caspase-1/11 play a role in amplifying inflammatory responses and reshaping the hepatic purinergic microenvironment during steatohepatitis progression, highlighting the P2X7 receptor as a potential therapeutic target in chronic liver disease.