In a groundbreaking fusion of cutting-edge technology and dermatological research, scientists at Biohub have unveiled novel therapeutic targets for psoriasis by conducting the first comprehensive genome-wide CRISPR screen in primary human adult skin cells. By overcoming the longstanding technical hurdle of delivering CRISPR components into notoriously resistant keratinocytes without toxicity, the team utilized centrifuge-based transfection to probe the genetic regulators involved in psoriasis, a chronic inflammatory skin disorder affecting millions globally.

This innovative approach involved knocking out approximately 19,000 genes in keratinocytes sourced from human donors using a vast CRISPR guide RNA library. The focus was on modulating IL17RA, a pivotal receptor that mediates skin inflammation, to chart a genome-wide landscape of genes influencing inflammatory pathways directly in the skin’s outermost layer. The resultant massive data set was then mined using an AI-driven model, VirtualCRISPR, which cross-referenced each gene’s significance against existing scientific literature to highlight previously unrecognized contributors to psoriasis pathology.

Strikingly, this AI-guided screen pinpointed two promising protein targets: ALOX5, an enzyme targeted by the asthma medication zileuton, and OXTR, the gene encoding for the oxytocin receptor, a surprising candidate unassociated before with skin inflammation. Validation experiments in 3D reconstructed human skin cultures demonstrated that zileuton modulates keratinocyte metabolism to suppress inflammation independently from immune cells, revealing a direct pharmacological avenue.

Importantly, topical formulations containing zileuton and cligosiban, an OXTR antagonist, were tested in a mouse model of psoriasis, achieving comparable efficacy to standard injected biologics that broadly suppress immune function. Beyond mitigating inflammation, OXTR inhibition appeared to restore skin barrier integrity—a crucial factor in chronic disease progression—spotlighting this receptor as a novel therapeutic axis.

Unlike current systemic therapies, which often carry risks of broad immunosuppression and high costs, these localized topical interventions promise targeted treatment with minimal systemic exposure. Moreover, the safety profiles of zileuton and OXTR antagonists are well-established in clinical settings, potentially accelerating their repurposing for dermatological applications.

This study exemplifies the transformative power of integrating AI with high-dimensional genetic screening to unravel complex disease mechanisms in cell types previously inaccessible to large-scale functional genomics. By enabling direct investigation into keratinocyte biology, the research not only charts a course for new psoriasis treatments but also sets a precedent for applying similar methodologies to other inflammatory conditions.

As psoriasis affects roughly 125 million people worldwide, innovations enabling precise, effective, and safer therapies could revolutionize patient care. Biohub’s approach heralds a new era where AI-guided CRISPR screens expedite the discovery of unexpected drug targets and foster the development of locally acting, biology-informed treatments.

Subject of Research: Psoriasis therapeutic targets via genome-wide CRISPR screening of human skin cells

Article Title: AI-guided CRISPR screening reveals therapeutic targets in psoriasis

News Publication Date: 8-Jul-2026

Web References:
https://www.nature.com/articles/s41467-026-75249-5

References:
DOI: 10.1038/s41467-026-75249-5

Image Credits: Biohub

Keywords

Psoriasis, CRISPR, Oxytocin receptor, ALOX5, Zileuton, Cligosiban, Keratinocytes, AI-guided screening, Inflammation, Topical therapeutics

Tags: 3D human skin culture validationAI-driven gene analysis in dermatologycentifuge-based transfection methodscomprehensive genomics in skin disease researchCRISPR delivery techniques in resistant skin cellsdiscovery of repurposable drugs for psoriasisGenome-wide CRISPR screening for psoriasisIL17RA pathway in psoriasiskeratinocyte gene regulationnovel drug targets for inflammatory skin diseasesOXTR gene and skin immune responserole of ALOX5 in skin inflammation