A multimodal analysis suggests partial IRF8/TLR7-associated myeloid transcriptional convergence between diabetic...

Diabetic kidney disease (DKD) and Parkinson's disease (PD) affect different organs but share epidemiological associations and innate immune abnormalities. The extent and cellular basis of reproducible cross-disease transcriptomic convergence remain uncertain.

Two DKD glomerular and three PD substantia nigra microarray cohorts were analyzed independently and combined using disease-specific and cross-disease meta-analysis. Independent DKD single-cell RNA-sequencing, PD single-nucleus RNA-sequencing, and spatial transcriptomic datasets were used for cell-type localization and donor- or sample-level analyses. CellChat, Monocle2, scTenifoldKnk, and previously generated UNAGI-compatible outputs were used to evaluate predicted intercellular communication, transcriptional-state continua, in-silico IRF8 perturbation, and compound prioritization. Threshold, leave-one-cohort-out, root-orientation, downsampling, and statistical-unit sensitivity analyses were performed where applicable.

The original nominal-threshold intersection of 36 genes was not retained after cohort-wise multiple-testing correction. Genome-wide overlap between DKD and PD was limited in the expanded analysis. IRF8 and TLR7 showed positive effect directions in both diseases but did not pass cross-disease false-discovery-rate correction and were therefore treated as exploratory candidates. Donor-level analyses did not detect statistically significant increases in broad myeloid-lineage proportions, although the confidence intervals did not establish equivalence. Selected DKD CCL and TNF interactions were retained in both of two targeted balanced-downsampling iterations, whereas the PD TGF-β signal was sampling-sensitive. Monocle2 identified branched and partially overlapping transcriptional-state continua. Spatial analyses provided marker-supported localization evidence without treating individual spatial observations as independent replicates. In-silico IRF8 deletion predicted regulatory-network changes but was not experimentally validated. NVP-AUY922 was the highest-ranked cross-disease computational candidate, but its association was not significant after correction across the matched compound universe.

DKD and PD show limited genome-wide overlap but partial convergence of myeloid- and microglia-enriched inflammatory signals associated with IRF8 and TLR7. These findings provide testable hypotheses rather than evidence of a conserved causal pathway or validated cross-disease treatment.