Plasma proteome–driven identification of druggable immune regulators of alopecia areata, validated by transcriptome and single-cell mapping

Background: Alopecia areata (AA) is an autoimmune hair-loss disorder driven by aberrant T-cell activation and immune–epithelial crosstalk. To identify actionable upstream regulators, we established a proteome-anchored multi-omics framework integrating genetic instruments, lesional transcriptomics, and single-cell immune profiling.Methods: Putative causal plasma proteins were prioritized using cis-pQTL–based inference across two large proteomic datasets (UKB-PPP; deCODE). Candidates were validated by differential expression in AA lesions, protein-interaction networks, and cell-type–resolved expression from scalp single-cell RNA-seq. Druggability was assessed using curated pharmacological resources, and PheWAS evaluated safety-relevant pleiotropy.Results: The pipeline identified 206 and 169 AA-associated proteins, with CD28, GZMB, and CD1C emerging as convergent immune regulators. Single-cell data showed enrichment of CD28⁺ effector T cells and CD1C⁺ myeloid subsets in lesions, linking circulating protein signals with local inflammation. Transcriptomic patterns implicated IL-2–modulated CD28 signaling and antihistamine-responsive pathways. Druggability analyses highlighted belatacept, a CD28-blocking biologic, while PheWAS indicated minimal adverse-phenotype enrichment.Conclusion: This proteome-driven framework uncovers druggable immune regulators of AA, positioning CD28 as an actionable target with a favorable safety profile and providing a generalizable strategy for autoimmune target discovery.