This study employed an integrative multi-omics strategy to investigate the potential role of inositol 1,4,5-trisphosphate receptor type 3 (ITPR3) in chronic prostatitis and to identify potential therapeutic targets and drugs using a Mendelian randomization (MR)-proteomics causal inference framework.
To investigate the potential role of ITPR3 in chronic prostatitis and to identify potential therapeutic targets and drugs.
We harmonized multi-omics data from eQTLGen (blood eQTLs, n = 31,684), UKB-PPP (plasma pQTLs, n = 54,219), and FinnGen (GWAS for chronic prostatitis: the discovery cohort 4,160 cases/130,139 controls and replication cohort 4,743 cases/141,300 controls). A two-sample bidirectional MR approach was applied to assess causal relationships between druggable genes and chronic prostatitis. The SMR-HEIDI analysis was conducted to exclude linkage disequilibrium confounding, followed by co-expression network construction and functional enrichment analysis to explore biological pathways. ITPR3 inhibitors were predicted using the DSigDB platform, with binding affinity evaluated through molecular docking and ADME properties analyzed via the SwissADME.
MR analysis revealed that each 1-standard deviation increase in genetically predicted ITPR3 expression was associated with a 32.8% higher risk of chronic prostatitis (OR = 1.328, 95% CI: 1.108-1.702, P < 0.001), which was further validated by SMR-HEIDI testing (HEIDI P > 0.05). Functional enrichment analysis suggested that ITPR3 may contribute to chronic prostatitis progression through TGF-β/SMAD7 inflammatory pathway and calcium signaling dysregulation, while co-expression network analysis indicated its association with Th17 cell differentiation. Molecular docking demonstrated high binding affinity between raloxifene and ITPR3, and ADME profiling indicated favorable oral bioavailability without significant CYP450 inhibition risk, complying with Lipinski's rule.
ITPR3 is a novel therapeutic target for chronic prostatitis, and the computational repurposing of raloxifene as its inhibitor warrants further experimental investigation. These findings provide new insights for developing clinical interventions in chronic prostatitis.
European journal of pharmacology. 2026 Jan 23 [Epub ahead of print]
Yutong Li, Xuan Dong, Ruixu Sun, Liangmeng Gao, Xingyu Song, Zhibin Huang, Ling Zuo, Hongwei Liu
Laboratory of Urology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China., Department of Traditional Chinese Medicine, The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang 524003., Department of Traditional Chinese Medicine, The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang 524003. Electronic address: ., Laboratory of Urology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China. Electronic address: .