AI-guided CRISPR screening reveals therapeutic targets in psoriasis.

Psoriasis affects over 125 million people globally. Biologics targeting the IL-17/IL-17RA axis are effective but require systemic administration, are costly, and are unsuitable for some patients. Developing topical small-molecule alternatives requires a better understanding of how IL-17 receptor A (IL17RA) is regulated in keratinocytes, the principal effector cells of psoriatic lesions. Here, we report a genome-wide CRISPR knockout screen for regulators of surface IL17RA in primary human epidermal keratinocytes. We prioritize hits using experimental enrichment together with VirtualCRISPR, a language-model framework trained on functional-genomics data, and validate two regulators with minimal prior connection to IL17RA: 5-lipoxygenase (ALOX5) and the oxytocin receptor (OXTR), which act through distinct cell-intrinsic mechanisms. Topical zileuton, an ALOX5 inhibitor, and cligosiban, an OXTR antagonist, suppress imiquimod-induced psoriasiform dermatitis in mice, mirroring systemic anti-IL17RA antibody efficacy. By linking AI- guided selection to genetic perturbation screening, this study provides an efficient route from candidate gene nomination to biological validation and therapeutic discovery.