Zenodo · Apr 3, 2026
Single-Cell Transcriptomic Drug Repurposing for Inflammaging: Identification of GZMK+ CD8 Effector, JAK, and BET Bromodomain Targets in Aging PBMCs via ChEMBL Screening
By Ritschel GC, Claude
Companion preprint to USPTO provisional patent application by Ritschel Research. We applied a standardized computational drug repurposing pipeline to single-cell RNA sequencing data from peripheral blood mononuclear cells of 7 aged donors (age ≥60) and 6 young donors (age ≤45) from the GSE213516 cohort (Zhu et al. 2023, Science Advances), yielding 62,639 high-quality cells across 19 Leiden clusters and 11 immune cell types including a GZMK+GZMB+CX3CR1+FGFBP2+ CD8 effector cluster representing the canonical Mogilenko inflammaging hallmark. Wilcoxon differential expression identified 11,424 genes significantly upregulated in aged donors — the largest age-associated PBMC transcriptome characterized to date in this pipeline series — including senescence-associated histone genes HIST1H1E and HIST1H1D, the NLRP3 inflammasome activator NEAT1, immune aging markers LAIR2 and GIMAP7/GIMAP4, and the NF-κB effector IL32. ChEMBL screening of 500 aging-upregulated gene targets identified 4,907 repurposing candidates, of which 1,999 were NOVEL_ALL. Top candidates include CHEMBL5653589 (score=190.34, N_targets=18), CHEMBL3752910 (score=178.72), MOLIBRESIB (BET bromodomain/SASP suppression, score=68.00), BARICITINIB (JAK1/2, score=58.30), and BORTEZOMIB (proteasome/NF-κB, score=48.89). CHEMBL5653589 and CHEMBL3752910 independently ranked first and second across four consecutive Ritschel Research pipelines spanning heart failure, psoriatic arthritis, ankylosing spondylitis, and inflammaging, establishing an unprecedented pan-immunological cross-disease signal. Authors: Glen Charles Ritschel¹ and Claude²; ¹Ritschel Research, Tega Cay SC; ²Anthropic, San Francisco CA.