Molecular characterization and functional prioritization of CD46, IL6R, KLRC1, LEAP2 and SMOX as candidate targets in acute kidney injury.

Acute kidney injury (AKI) remains a critical condition with limited pharmacological options. Bioactive molecules, including cytokines, receptors, and enzymes, play central roles in AKI pathogenesis, but systematic efforts to identify translational targets remain limited. In this study, we implemented a multi-omics integrative framework to nominate and validate candidate targets for AKI. Using genetically informed screens anchored on a curated set of potentially actionable genes, we identified five prioritized candidates, CD46, IL6R, KLRC1, LEAP2, and SMOX, with strong biological plausibility and therapeutic potential. Bulk and single-cell RNA sequencing data revealed cell-type-specific enrichment, particularly in proximal tubules, immune subsets, and endothelium under AKI conditions. Pathway enrichment highlighted shared involvement in cytokine signaling, antigen presentation, and metabolic stress responses. In silico drug repurposing revealed several clinically approved compounds (e.g., tacrine, raloxifene hydrochloride, tretinoin) with strong predicted binding to CD46, IL6R, and SMOX. In vivo experiments demonstrated that pharmacological inhibition of SMOX significantly alleviated tubular injury, preserved renal function, and reduced oxidative stress. In vitro studies further confirmed the protective effects of SMOX inhibition by maintaining epithelial cell integrity and viability in renal tubular cells, while suppressing oxidative damage.