Cross-Cohort, Renal Compartment-Aware Transcriptomic Assessment of Lycii Fructus-Annotated Targets in Diabetic Kidney Disease

Diabetic kidney disease (DKD) differs transcriptionally across renal compartments. We assessed whether Lycii Fructus-annotated targets showed reproducible DKD-associated changes and enrichment beyond matched expectations. Linked glomerular (GSE30528) and tubulointerstitial (GSE30529) cohorts were used for discovery; GSE96804 and platform-specific GSE104954 subsets provided external assessment. Phenotype-independent probe aggregation preceded limma analysis. Of 106 standardized HERB targets, 91 were measurable. Specificity was tested by hypergeometric analysis and 10,000 expression- and publication-matched permutations; external evidence was graded symmetrically. Thirty-six targets met the primary criterion in at least one compartment, but the target set was not enriched. CASP8 and VEGFA met Tier A external criteria, whereas ADRB2 and SLC6A2 met Tier B criteria. At the stricter |log2FC| ≥ 0.585 threshold, ADRB2 passed in both discovery compartments, VEGFA only in glomeruli, and CASP8/SLC6A2 in neither. STRING analysis used the measured-gene background. Reference redocking reproduced carazolol in ADRB2 and atomoxetine in SLC6A2 (RMSD, 1.08 and 1.09 Å). Thus, the four genes are reproducible DKD-perturbed candidates carrying Lycii Fructus annotations, not evidence of a Lycii Fructus-specific mechanism; they warrant targeted pharmacological testing.