Identification of druggable targets in acute kidney injury by proteome- and transcriptome-wide Mendelian randomization and bioinformatics analysis.

Abstract

Background: Acute kidney injury (AKI) remains a critical condition with limited therapeutic options, predominantly managed by renal replacement therapy. The challenge of developing targeted treatments persists.

Methods: We integrated genetic data related to druggable proteins and gene expression with AKI genome-wide association study (GWAS) findings. Based on multi-omics Mendelian randomization (MR), we identified the potential causal influence of 5,883 unique proteins and genes on AKI. We also performed using reverse MR and external cohort-based analysis to verify the robustness of this causal relationship. Expression patterns of these targets were examined using bulk transcriptome and single-cell transcriptome data. In addition, drug repurposing analyses were conducted to explore the potential of existing medications. We also constructed a molecular interaction network to explore the interplay between identified targets and known drugs.

Results: Genetically predicted levels of seven proteins and twelve genes were associated with an increased risk of AKI. Of these, six targets (NCF1, TNFRSF1B, APEH, ACADSB, ADD1, and FAM3B) were prioritized based on robust evidence and validated in independent cohorts. Reverse MR showed a one-way causal relationship of targets. These targets are predominantly expressed in proximal tubular cells, endothelial cells, collecting duct-principal cells, and immune cells within both AKI-affected and normal tissues. Several promising drug repurposing opportunities were identified, such as telmisartan-NCF1, calcitriol-ACADSB, and ethinyl estradiol-ACADSB. The molecular interaction mapping and pathway integration analysis provided further insights, suggesting potential strategies for combinatorial therapies.

Conclusions: This extensive investigation identified several promising therapeutic targets for AKI and highlighted opportunities for drug repurposing. These findings offer valuable insights that could shape future research and the development of targeted treatments.