Oxidative Stress-Related Targets POR and MAPK13 Elucidated for Sarcoidosis Therapy Through Multiomics Analysis

Abstract

Purpose: We aimed to identify potential plasma protein targets genetically associated with oxidative stress genes in sarcoidosis.

Methods: We performed summary data-based Mendelian randomization (SMR) analyses using summary statistics from the FinnGen cohorts and multiomics data on quantitative trait loci (QTLs) linked to oxidative stress genes at protein, RNA, and methylation levels. We validated the findings with two independent datasets from published studies. Bayesian colocalization analysis confirmed shared genetic bases and excluded pleiotropy. We also identified relevant plasma regulatory transcription factors (TFs) and constructed protein–protein interaction (PPI) networks. In addition, molecular docking was conducted for drug ligand-protein binding assays.

Results: MAPK13 and POR were identified as significant in proteome-wide SMR, transcriptome-wide SMR, and methylation-wide SMR analyses. These findings were validated through Bayesian colocalization and confirmed in two additional sarcoidosis cohorts. In PSMR analysis, the A allele of rs10447396 near MAPK13 (p38δ) (p = 0.0068 and β = 0.6009) and the A allele of rs59882870 at POR (p = 0.0006 and β = 0.3924) were associated with increased sarcoidosis risk. NFATC3 and NFKB1 were identified as common TFs influencing MAPK13 and POR expression in plasma. Molecular docking identified two potential MAPK13-targeting drugs, ilorasertib and SNS-314, both showing strong affinities for MAPK13.

Conclusion: This study is the first to identify MAPK13 and POR as potential drug targets for sarcoidosis. In addition, molecular docking preliminarily identified potential therapeutic compounds targeting these proteins, suggesting avenues for future experimental validation and the potential development of targeted therapies.