Distinct Molecular Relationships and Partial Pathway Convergence of Anserine and RRR-α-Tocopherol in Human Diabetic Kidney Disease

Diabetic kidney disease (DKD) involves interacting metabolic, inflammatory, vascular, and fibrotic disturbances. This study investigated the molecular relationships of anserine and RRR-α-tocopherol with human DKD using a disease-centered computational framework in which compound–target evidence was established independently before integration with kidney transcriptomic data. Stage-associated transcription was analyzed in 36 human kidney samples spanning Control, Early DKD, and Advanced DKD, with external assessment in two independent cohorts, followed by evidence-based prioritization, pathway analysis, renal single-cell localization, and sensitivity analyses. Predefined target sets comprised 100 anserine and 111 RRR-α-tocopherol targets, with only 16 shared. Integration yielded 21 prioritized compound–DKD relationships involving 20 unique genes. Despite limited target overlap, the primary pathway analysis identified shared enrichment in Class A G protein-coupled receptor, Gαi, interleukin, and receptor tyrosine kinase signaling; only receptor tyrosine kinase signaling remained shared under conservative target-confidence restriction. The 20 genes localized across diverse tubular, immune, vascular, and stromal populations. Sensitivity analyses retained 17 of 21 relationships under stricter target-confidence criteria and showed external gene–DKD replication for 18 of 21 relationships in at least one cohort. These findings define a transparent, hypothesis-generating framework for experimental testing without implying therapeutic efficacy or a confirmed mechanism of action.