Vivian Bui

Background: Psoriasis is an autoimmune disorder that impacts 2-3% of the global population which is estimated to be about 125 million people.^1,2 Polymorphism of the HLA-class 1 allele (HLA-C*06:02) on the Psoriasis Susceptibility Locus 1 (PSORS1) demonstrates the highest genetic risk of psoriasis.³ Current treatments target the IL-23/IL17 axis.² Untreated psoriasis with comorbidities significantly increases risk for prolonged inflammation of major organ systems. First-line treatment for moderate-to-severe psoriasis is IL-17A inhibitors. Although onset is fast, they require frequent and large doses.³ TNF inhibitors are also approved for plaque psoriasis, but there are concerns of severe bacterial or viral infections and increased risk of cancer.³ There is no known cure for psoriasis and treatment is a life-long procedure.¹ Due to the multitude of factors influencing psoriasis and its severity, some patients do not respond to the current drug treatments which suggest research for alternative drug targets.⁵

Objective: In this narrative review, we analyzed known mechanisms causing psoriasis vulgaris and explored new drug targets.

Search methods: An online search in the PubMed database was conducted from 2018 to 2025 using the following keywords: “psoriasis vulgaris”, “psoriasiform inflammation”, and “keratinocyte hyperproliferation”.

Results: Studies found that elevated IL-17A, IFN- γ, and IL-6 levels in serum and skin lesions were a biomarker for inflammatory responses in psoriasis patients.⁶ IL-17 signaling is an essential pathway in development of IMQ-induced inflammation and DMBA/TPA-induced papillomas in psoriatic-like skin.⁷ IL-17rc knockout mice were shown to have reduced psoriasiform symptoms and tumor formation compared to WT groups.⁷ Genetic defects of IL-17 signaling significantly reduced suppression of IMQ-induced epidermal hyperplasia and completely blocked DMBA/TPA-induced papilloma formation.⁷ Studies have found that IL-17A activates the Hippo-YAP pathway by recruiting MST1 to ACT1 which disrupts the MST1-LATS1 interaction.⁸ This causes a reduction in LATS1-mediated phosphorylation of YAP which leads to activated YAP enzyme. Active YAP upregulates AREG which increases keratinocyte proliferation in vitro leading to epidermal hyperplasia in psoriatic lesions and IMQ/IL-17A-treated mouse skin. Inhibition of the IL-17A or YAP suppresses Yap activation which reduced hyperplasia in mice models.⁸ New treatments such as hyaluronic acid, Treg exosomes, and dimethyl fumarate were have good biocompatibility and reduce systemic exposure to the drug compared to standard oral or high-dose systemic treatments.⁶ Patch treatment also shifted the immune balance by suppressing Th17 cells while promoting Tregs and tolerogenic dendritic cells locally and systemically.⁶ 

Conclusions: Recent evidence refutes centrosome amplification as a driver of keratinocyte proliferation.⁷ IL-17–targeted therapies, including microneedle patch delivery, reduce inflammation, immune cell chemotaxis, and epidermal hyperproliferation in murine models.⁶ IκBζ has emerged as a critical effector linking IL-17 and IL-36 signaling pathways.^9,10 Its deletion reduces inflammation and epidermal hyperplasia, and its presence in dermal fibroblasts supports a broader role in disease pathogenesis.^9,10 Together, these findings identify IκBζ and IL-36 as promising targets for future localized, less invasive psoriasis therapies.^6,9,10

Works cited:

1. Yao Y, Chen LQ, Lv YB, et al. Skin immune microenvironment in psoriasis: from bench to bedside. Front Immunol. 2025;16:1643418. doi:10.3389/fimmu.2025.1643418
2. Potestio L, Fabrizio Martora, Lauletta G, Vallone Y, Battista T, Megna M. The Role of Interleukin 23/17 Axis in Psoriasis Management: A Comprehensive Review of Clinical Trials. Clinical, cosmetic and investigational dermatology. 2024;Volume 17:829-842. doi: https://doi.org/10.2147/ccid.s462797
3. Hawkes JE, Yan BY, Chan TC, Krueger JG. Discovery of the IL-23/IL-17 Signaling Pathway and the Treatment of Psoriasis. J Immunol. 2018;201(6):1605-1613. doi:10.4049/jimmunol.1800013
4. Lisa B LL, Petrovic A, Krogh Aarebrot A, Appel S. The TNF/IL‐23/IL‐17 axis—Head‐to‐head trials comparing different biologics in psoriasis treatment. Scandinavian Journal of Immunology. 2020;92(4). doi: https://doi.org/10.1111/sji.12946
5. ‌Griffiths CEM, Armstrong AW, Gudjonsson JE, Barker JNWN. Psoriasis. Lancet (London, England). 2021;397(10281):1301-1315. doi:https://doi.org/10.1016/S0140-6736(20)32549-6
6. ‌Ou M, Cao J, Luo R, et al. Drug-loaded microneedle patches containing regulatory T cell-derived exosomes for psoriasis treatment. Acta Biomaterialia. 2025;198:452-466. doi:https://doi.org/10.1016/j.actbio.2025.04.015
7. Jin B, Zhang Y, Miller HD, et al. Defect of IL17 Signaling, but Not Centrinone, Inhibits the Development of Psoriasis and Skin Papilloma in Mouse Models. Biomedicines. 2022;10(8):1976. Published 2022 Aug 15. doi:10.3390/biomedicines10081976
8. Yu C, Yu N, Li Z, et al. IL-17A promotes psoriasis-associated keratinocyte proliferation via ACT1-dependent activation of YAP and amphiregulin. J Invest Dermatol. 2022;142(12):3219-3230.e7.
9. Müller, A. Hennig, S. Lorscheid, P. Grondona, K. Schulze-Osthoff, S. Hailfinger, & D. Kramer, IκBζ is a key transcriptional regulator of IL-36–driven psoriasis-related gene expression in keratinocytes, Proc. Natl. Acad. Sci. U.S.A. 115 (40) 10088-10093, https://doi.org/10.1073/pnas.1801377115 (2018)
10. Lorscheid S, Müller A, Löffler J, et al. Keratinocyte-derived IκBζ drives psoriasis and associated systemic inflammation. JCI Insight. 2019;4(22):e130835. Published 2019 Nov 14. doi:10.1172/jci.insight.130835