Plasma Proteome-Driven Identification of Druggable Immune Regulators of Alopecia Areata, Validated by Transcriptome and Single-Cell Mapping

Introduction: 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-protein quantitative trait loci-based inference across two large proteomic datasets (UKB-PPP and 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: 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.