{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T16:18:33Z","timestamp":1778602713970,"version":"3.51.4"},"reference-count":65,"publisher":"S. Karger AG","license":[{"start":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T00:00:00Z","timestamp":1773187200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/karger.com\/pages\/terms-and-conditions"},{"start":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T00:00:00Z","timestamp":1773187200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/karger.com\/pages\/terms-and-conditions"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Skin Appendage Disord"],"abstract":"<jats:p>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: 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.<\/jats:p>","DOI":"10.1159\/000551293","type":"journal-article","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T17:00:51Z","timestamp":1773248451000},"page":"1-17","source":"Crossref","is-referenced-by-count":0,"title":["Plasma Proteome-Driven Identification of Druggable Immune Regulators of Alopecia Areata, Validated by Transcriptome and Single-Cell 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