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

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.