Therapeutic potential of roxadustat in immune thrombocytopenia: A Mendelian randomization analysis

Background: Immune thrombocytopenia (ITP) is characterized by immune-mediated platelet destruction and impaired megakaryocyte maturation. Hypoxia-inducible factor-1 alpha (HIF-1α), pivotal in the development of megakaryocytes and immune regulation, is downregulated in ITP. Roxadustat, which stabilizes HIF-1α, has emerged as a potential therapeutic drug for ITP that acts by enhancing HIF-1α-mediated megakaryocyte development and modulating immune responses.

Objectives: This study evaluates the safety profile of roxadustat and its therapeutic efficacy for ITP treatment using Mendelian randomization (MR) analysis.

Methods: We used expression Quantitative Trait Loci (eQTLs) data for roxadustat's target genes (EGLN1, EGLN2, EGLN3) and genetic associations with ITP, and adverse outcomes from the Open Genome-Wide Association Study (OpenGWAS) project. MR analysis included IVW, MR-Egger regression, weighted median, and MR pleiotropy residual sum and outlier (MR-PRESSO) methods to evaluate pleiotropy. Heterogeneity was assessed using Cochran's Q statistic and I² measure, with sensitivity analyses. A meta-analysis was performed to integrate effect sizes from multiple literature sources.

Results: MR analysis revealed a significant association between roxadustat and reduced ITP risk (odds ratio [OR] 0.79, 95% confidence interval [CI] 0.66-0.95, P=0.01) with no evidence of horizontal pleiotropy. Meta-analysis confirmed the protective effect of roxadustat on ITP. Utilizing eQTLs of roxadustat's target gene EGLN1 as instrumental variables, an MR analysis of 39 potential adverse reactions revealed no significant increase, suggesting a favorable safety profile for roxadustat.

Conclusion: Roxadustat demonstrates a potential protective effect against ITP without increasing the risk of adverse outcomes, suggesting its promise as a therapeutic option for ITP and warranting further investigation.