Druggable Targets for Pelvic Inflammatory Disease: Mendelian Randomization and Experimental Validation.

Abstract

Background: Pelvic inflammatory disease (PID) is a common gynecological disorder that seriously affects women's physical and mental health, yet there are few effective therapeutic options.

Objective: Mendelian randomization (MR) has been used to repurpose existing drugs and identify new therapeutic targets. Therefore, we performed a systematic drugable genome-wide MR analysis to explore potential therapeutic targets for PID.

Methods: We utilized cis-expressed quantitative trait loci (cis-eQTL) of druggable genes and PID Genome-Wide Association Study (GWAS) data to perform MR analysis and colocalization analysis, screened candidate drugs through drug prediction, identified the most stable druggable genes with the highest binding affinity through molecular docking, and finally constructed a PID rat model to validate gene expression.

Results: MR analysis, colocalization analysis, and protein interaction analysis identified six key genes. Drug enrichment analysis and molecular docking revealed two potential drugs (Sunitinib and Everolimus) targeting Albumin (ALB), Interleukin 6 (IL6), and Cluster of Differentiation 4 (CD4). In the PID rat model, ALB and IL6 expression decreased, while CD4 expression increased.

Conclusion: Our MR analysis provides genetic evidence supporting ALB, IL6, and CD4 as druggable genes for PID treatment. Among the drug candidates with repurposing opportunities targeting the above genes, Sunitinib and Everolimus were effective. Subsequent in vivo experiments validated the differential expression of ALB, IL6, and CD4 in PID rats.