Integrated Multi-Omics Analysis Reveals the Mechanisms of Naringin in Ameliorating High-Fat Diet-Induced Metabolic Dysfunction-Associated Steatotic Liver Disease

Wenping Sun¹Na Xue²Qiang Zhang^3*

• ¹Gansu Provincial Hospital, Lanzhou, China
• ²Gansu University of Chinese Medicine, Lanzhou, China
• ³Department of Pathology, Gansu Provincial Hospital, Lanzhou,, Gansu, China

Naringin (Nar), the predominant flavonoid in citrus fruits, shows therapeutic potential against Metabolic dysfunction-associated steatotic liver disease (MASLD), yet its underlying mechanisms remain largely elusive. Here we investigated the efficacy and underlying mechanisms of Nar in a mouse model of high-fat diet (HFD)-induced MASLD, employing integrated analyses of hepatic lipidomics and gut microbiota. Treatment with Nar markedly ameliorated MASLD phenotypes, evidenced by reduced body and liver weights, lower hepatic triglycerides (TGs), and improved serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Network pharmacology analysis revealed that Nar targets associated with MASLD disease are primarily enriched in SRC, AKT1, SRC, STAT3, FOS, ESR1, and NFKB1, which exert their effects through the PI3K-AKT signaling pathway. Molecular docking simulations further elucidated the interaction mechanisms. Lipidomic analysis further revealed that Nar restored hepatic lipid homeostasis, significantly decreasing levels of TGs and diglycerides (DGs), with 20 differentially abundant lipid species identified as potential biomarkers. Additionally, Nar profoundly altered the gut microbial community, promoting the enrichment of beneficial genera including Oscillibacter, Allisonella, and Flavonifractor. Our findings indicate that Nar prevents MASLD by harmonizing hepatic lipid metabolism and modulating the gut microbiome.