Identification of DHX58 as a potential therapeutic target for ovarian cancer through multi-omics Mendelian randomization and transcriptomic data analysis

Ovarian cancer (OC), a prevalent malignancy of the female reproductive system, is significantly impacted by drug resistance, which reduces treatment efficacy and worsens patient survival. Therefore, identifying broader therapeutic targets is crucial for improving treatment outcomes in OC patients. The research project utilized Mendelian randomization (MR) analysis and summary data-based Mendelian randomization (SMR) to identity potential treatment targets for OC. The eQTLGen collaboration provided the cis-expression quantitative trait locus data, while the Genotype-Tissue Expression (GTEx) project v8 provided the ovarian tissue eQTL data. Protein quantitative trait locus (pQTL) was generated by the INTERVAL, Fenland, and SCALLOP studies. The open-access genome-wide association study (ID: GCST90018888), involving a European population, provided the summary statistics for OC. Additionally, colocalization analyses were employed to determine wether the same SNPs drive the expression of genes and OC risk, and transcriptomic and Single-cell RNA sequencing data analysis was utilized to further investigate the targets clinical significance of these in OC. To evaluate its potential for drug development, drug prediction and molecular docking analyses were also carried out. In the SMR analysis, DHX58 was significantly associated with all three omics levels. The MR results indicated a correlation between elevated OC risk and DHX58 (OR = 1.300; 95% CI = 1.120–1.510; P = 0.000). Colocalization analysis further supported this finding (PP.H4 = 0.949). Our results revealed that DHX58 expression was significantly associated with patient prognosis, enriched immune-related pathways, and distinct immune cell infiltration patterns. PheWAS at the gene level revealed no significant correlation between DHX58 and additional phenotypes. The molecular docking results revealed strong interactions between DHX58 and other drugs and proteins with known structural information. This study confirmed a significant correlation between DHX58 and OC, indicating that DHX58 could be a viable target for OC treatment. Drugs targeting DHX58 are likely to have higher success rates in clinical trials, providing new directions for future clinical and basic research.