AI-guided CRISPR identifies ALOX5 and OXTR as IL17RA regulators; topical zileuton and cligosiban suppress psoriasis

Psoriasis affects over 125 million people globally, characterized by chronic skin inflammation. Current biologics targeting the IL-17/IL-17RA axis are effective but require systemic administration, are costly, and are not suitable for all patients. This creates a significant gap for topical small-molecule alternatives. A deeper understanding of how IL17RA is regulated in keratinocytes, the primary effector cells in psoriatic lesions, is crucial for developing such targeted therapies.

Researchers conducted a genome-wide CRISPR knockout screen to identify regulators of surface IL17RA in primary human epidermal keratinocytes. They prioritized hits using experimental enrichment combined with VirtualCRISPR, an AI language-model framework trained on functional-genomics data. Two prioritized regulators, ALOX5 and OXTR, were then validated. To assess therapeutic potential, topical zileuton, an ALOX5 inhibitor, and topical cligosiban, an OXTR antagonist, were administered in a mouse model of imiquimod-induced psoriasiform dermatitis. The efficacy of these topical treatments was compared to that of systemic anti-IL17RA antibody.

The AI-guided CRISPR screen successfully identified novel regulators of IL17RA expression. Specifically, 5-lipoxygenase (ALOX5) and the oxytocin receptor (OXTR) were validated as key regulators of surface IL17RA in keratinocytes. These two targets were found to act through distinct cell-intrinsic mechanisms, previously having minimal connection to IL17RA regulation. The therapeutic potential was confirmed in vivo:

Topical zileuton, an ALOX5 inhibitor, significantly suppressed imiquimod-induced psoriasiform dermatitis in mice. Similarly, topical cligosiban, an OXTR antagonist, also suppressed psoriasiform dermatitis in the mouse model. Importantly, the efficacy observed with these topical small molecules mirrored that of systemic anti-IL17RA antibody treatment, suggesting a comparable therapeutic effect via a localized delivery route.