Prognostic Significance and Mechanistic Insights of Rutin-Related Ferroptosis Gene Signature in Hepatocellular...

This study aims to elucidate the anti-tumor properties of rutin and its specific molecular mechanisms for inhibiting hepatocellular carcinoma (HCC) through the ferroptosis.

The effects of rutin on HuH-7 cell proliferation, migration, invasion, and cell cycle progression were evaluated through in vitro experiments. By integrating bioinformatics analysis and network pharmacology, potential ferroptosis targets influenced by rutin in HCC were identified from the TCGA-LIHC database. A prognosis-related risk-scoring model was constructed and validated in the GEO14520 cohort and ICGC-LIRI-JP. Samples were categorized into high-risk and low-risk groups based on their scores. Enriched pathways within these different risk groups were explored using Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA). Additionally, key targets of rutin-related ferroptosis in HCC cells were investigated through single-cell analysis and molecular docking studies.

Rutin inhibited the proliferation, invasion, migration, and cell cycle progression of HCC cells in a dose-dependent manner. We constructed a risk model comprising five ferroptosis-related targets of rutin (FRTs-R): ACACA, AKR1C3, ALDH2, AR, and CDK1. This prognostic model was validated in the GEO14520 and ICGC datasets, revealing that the low-risk group had a better prognosis than the high-risk group. Furthermore, lipid metabolism pathway activity was up-regulated in the low-risk group. Single-cell analysis indicated specific expression of AKR1C3 in HCC cells, while molecular docking analysis showed that, among the five potential targets, AKR1C3 demonstrated the most stable binding affinity to rutin.

Our findings suggest that rutin may modulate ferroptosis in HCC, with rutin associated ferroptosis genes implicated in disease biology; moreover, the proposed risk scoring model shows promising prognostic utility in HCC.