# Causal Effects of a Hepatic Senescence Gene Set on MASLD Fibrosis: A Mendelian Randomization Study and Quercetin Molecular Docking Analysis

## TL;DR

This study explores how a set of liver aging genes affects liver disease progression and suggests quercetin may help reduce liver fibrosis.

## Contribution

The study identifies GBP2 as a causal gene in liver fibrosis and cholangiocarcinoma and proposes quercetin as a potential modulator.

## Key findings

- GBP2 expression is a risk factor for liver fibrosis but protective against cholangiocarcinoma.
- Quercetin may indirectly suppress GBP2 via IRF1, potentially reducing liver aging.
- GBP2 correlates negatively with macrophages in fibrosis and positively with T and NK cells in cholangiocarcinoma.

## Abstract

Background: The senescence-associated hepatic gene set (SHGS) is critical in metabolic-dysfunction-associated steatotic liver disease (MASLD) progression. However, causal links between SHGS genes and liver diseases remain unclear. Methods: Mendelian randomization (MR) was used to explore causal relationships between SHGS genes and liver diseases. Immune infiltration of key genes was analyzed using the CIBERSORT algorithm with GEO database data, validated by single-cell RNA sequencing (scRNA-seq). Virtual docking assessed quercetin’s potential to modulate SHGS proteins and mitigate liver aging. Results: MR analysis identified elevated GBP2 expression as a risk factor for liver fibrosis (OR = 1.904, p = 0.028) but protective against cholangiocarcinoma (OR = 0.548, p = 0.001). Immune profiling and scRNA-seq revealed GBP2’s negative correlation with macrophages in fibrosis and positive correlations with T and NK cells in cholangiocarcinoma. Molecular docking suggested that quercetin indirectly suppresses GBP2 via IRF1, potentially attenuating liver aging. Conclusions: GBP2 might modulate hepatic fibrosis and cholangiocarcinoma. Quercetin may exert antifibrotic effects by indirectly modulating GBP2.