Researchers explored the potential of using a selective TYK2 inhibitor, BMS-986165, as a topical treatment for psoriasis—a novel approach compared to its recently approved oral formulation. Using a mouse model of imiquimod-induced psoriatic dermatitis, researchers applied a 1.5% BMS-986165 ointment to evaluate its therapeutic effects. The topical formulation significantly reduced psoriasis-like symptoms and inflammation. Single-cell RNA sequencing and flow cytometry revealed that keratinocytes (KCs)—key skin cells in psoriasis—were major targets of the topical TYK2 inhibitor.

Further in vitro experiments showed that inhibiting TYK2 disrupted the AKT-SP1 signaling pathway, leading to decreased expression of the nerve growth factor receptor (NGFR) and reduced activation of AP1, a protein complex involved in proinflammatory signaling. These findings suggest that topical TYK2 inhibition directly reduces the inflammatory capabilities of keratinocytes, a key driver of psoriasis. This research highlights a promising new route for psoriasis treatment via topical TYK2 inhibition and uncovers a previously underexplored mechanism in keratinocyte-driven inflammation.

Reference: Fang Z, Jiang R, Wang Y, et al. Topical TYK2 inhibitor ameliorates psoriasis-like dermatitis via the AKT-SP1-NGFR-AP1 pathway in keratinocytes. Clin Transl Med. 2025 Mar;15(3):e70256. doi: 10.1002/ctm2.70256. PMID: 40038877; PMCID: PMC11879890.