Hepatoprotective Effects of Maillard Reaction Products From Perinereis aibuhitensis : Identification and Metabolomic Insights in a Mouse Model of Alcoholic Liver Disease

ABSTRACT Alcoholic liver disease (ALD) is a major global health burden with limited therapeutic options. The primary aim of this study was to investigate the hepatoprotective effects of Maillard reaction products derived from Perinereis aibuhitensis (P‐MRPs) in a mouse model of chronic alcohol‐induced liver injury. Male ICR mice were fed a Lieber–DeCarli alcoholic liquid diet for 6 weeks with or without P‐MRPs administration. P‐MRPs intervention significantly reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, alleviated hepatic histopathological injury, restored antioxidant enzyme activities (superoxide dismutase and glutathione peroxidase), and lowered malondialdehyde and interleukin (IL‐6, IL‐18, and IL‐1β) levels. Mechanistically, P‐MRPs treatment upregulated hepatic nuclear factor erythroid 2‐related factor 2 (NRF2), downregulated NF‐κB p65 and tumor necrosis factor (TNF)‐α, and restored carnitine O‐palmitoyltransferase 1A (CPT1A) expression. Liver metabolomic analysis revealed that P‐MRPs administration increased N‐acyl amino acids and tryptophan‐derived metabolites while reversing alcohol‐induced accumulation of glycerophospholipids and acylcarnitines. In vitro, P‐MRPs reduced ethanol‐induced ROS accumulation and attenuated ALT and AST leakage in AML12 hepatocytes. Compositional profiling identified 27 small‐molecule compounds with significant changes in P‐MRPs abundance, and a high proportion of small‐molecule peptides. Collectively, these findings suggest that P‐MRPs protect against ALD‐related liver injury, potentially through coordinated regulation of antioxidant, inflammatory, and lipid metabolic pathways, and provide a hypothesis‐generating framework for future mechanistic investigations.