# Integrated multi-omics analysis reveals the mechanisms of naringin in ameliorating high-fat diet-induced metabolic dysfunction-associated steatotic liver disease

## TL;DR

Naringin, a citrus flavonoid, helps reduce liver disease caused by high-fat diets by balancing liver lipids and improving gut microbes.

## Contribution

This study reveals naringin's novel therapeutic mechanisms in MASLD through integrated multi-omics analysis.

## Key findings

- Naringin reduces liver weight, triglycerides, and improves liver enzyme levels in mice with MASLD.
- Naringin targets key proteins like SRC and AKT1 via the PI3K-AKT pathway to combat MASLD.
- Naringin alters gut microbiota, promoting beneficial genera like Oscillibacter and Flavonifractor.

## Abstract

Naringin (Nar), the predominant flavonoid in citrus fruits, shows therapeutic potential against metabolic dysfunction-associated steatotic liver disease (MASLD). However, its underlying mechanisms remain largely elusive.

In this study, we investigated the efficacy and underlying mechanisms of Nar in a mouse model of high-fat diet (HFD)-induced MASLD using integrated analyses of network pharmacology, molecular docking, hepatic lipidomics, and gut microbiota.

Treatment with Nar markedly ameliorated MASLD phenotypes, as 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 are primarily enriched in proteins such as SRC, AKT1, 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 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, providing a multifaceted mechanistic insight into its therapeutic potential.