AI-guided CRISPR study identifies potential topical psoriasis treatments

An AI-guided network analysis of genomic data (left) highlights two protein targets, including the oxytocin receptor, identified through Biohub’s CRISPR screen in primary human skin cells (right). Image by Zhao, C., Shih, M., Ahmed, S. et al. Nat Commun (2026).

Researchers have combined genome-wide CRISPR screening with artificial intelligence to identify two unexpected therapeutic targets for psoriasis, opening a possible path toward topical treatments that avoid systemic immunosuppression.

The study, published in Nature Communications, examined regulation of interleukin-17 receptor A (IL17RA) in primary human epidermal keratinocytes. IL17RA helps mediate inflammatory signalling implicated in psoriasis.

Using approximately 77,000 guide RNAs, the researchers disrupted about 19,000 genes individually in keratinocytes from two human donors. They then measured the effects on cell-surface IL17RA.

To distinguish potentially novel targets from genes already associated with known inflammatory pathways, the investigators used VirtualCRISPR, a language-model framework trained on published functional-genomics data. The analysis prioritized two genes with limited previous connections to IL17RA: ALOX5, which encodes 5-lipoxygenase, and OXTR, which encodes the oxytocin receptor.

“A CRISPR screen at this scale, guided by AI, gave us answers the field has never had access to before, as well as a surprisingly effective potential treatment,” said Shana O. Kelley, president of bioengineering and head of the Chicago-based biomedical research organization Biohub in a press release.

The researchers subsequently evaluated zileuton, an ALOX5 inhibitor approved for asthma, and cligosiban, an OXTR antagonist. In three-dimensional human skin cultures, zileuton suppressed inflammatory and proliferative gene programs through a direct effect on keratinocytes, without requiring immune cells.

Topical gel formulations of both compounds were then tested in mice with imiquimod-induced psoriasiform dermatitis. Within five days, both treatments reduced disease severity. After one week, their effects were comparable to those of a systemically administered anti-IL17RA antibody, including normalization of skin thickness and a shift toward anti-inflammatory immune-cell signalling.

Cligosiban produced the broadest restoration of skin tissue, suggesting that OXTR inhibition could potentially address epidermal barrier dysfunction as well as inflammation.

The findings are preclinical, and efficacy and safety in people with psoriasis have not been established. Nevertheless, the availability of previous human safety data for zileuton and OXTR antagonists could help support further investigation.

“We think of this as a blueprint,” said Abdalla M. Abdrabou, lead scientist for Biohub’s Functional Immunogenomics group. “The specific targets we found in psoriasis are exciting, but the method itself is what we are most proud of. This is a generalizable way to find treatments that those of us studying disease wouldn’t even know to look for.”