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Lookup NU author(s): Dr Kirsty HodgsonORCiD, Dr Joe InnsORCiD, Dr Gary ReynoldsORCiD, Emily Stephenson, Naomi Sinclair, Dr Andrew FreyORCiD, Dr Iglika Ivanova, Dr Simon CockellORCiD, Dr Jonathan Coxhead, Professor Matthias TrostORCiD, Professor Muzlifah Haniffa, Professor Neil PerkinsORCiD, Professor Neil RajanORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2026. Published by Oxford University Press on behalf of British Association of Dermatologists. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.Background: CYLD cutaneous syndrome (CCS) skin tumours develop from puberty onwards, can number in the hundreds and progressively grow over time. Patients with CCS lack medical therapies and require repeated surgery to control tumour burden. CYLD loss of heterozygosity drives tumour growth, and CCS tumours have previously been shown to demonstrate increased canonical nuclear factor kappa B (NF-κB) and Wnt signalling. Objectives: To investigate NF-κB signalling in CCS tumours and CCS tumour keratinocytes, with the aim of identifying druggable targets. Methods: We used complementary bulk transcriptomics and proteomics in patient-derived CCS tumour cell fractions, as well as single-cell RNA sequencing of CCS tumour cells to investigate aberrant NF-κB signalling. We developed a patient-derived CCS tumour spheroid culture model to determine the utility of targeting aberrant NF-κB cell signalling. Results: We demonstrate evidence of non-canonical NF-κB signalling in CCS tumour keratinocytes, with increased p100 to p52 processing and RelB protein expression compared with normal skin. We identify IκB kinase alpha (IKKα) as a candidate target in the noncanonical NF-κB signalling pathway. A novel, highly selective IKKα inhibitor (SU1644) used in patient-derived CCS tumour spheroid cultures demonstrated that IKKα inhibition reduced tumour spheroid viability. Conclusions: These data provide the preclinical rationale for the assessment of topical IKKα inhibitors as a novel preventive treatment for CCS.
Author(s): Hodgson K, Inns J, Reynolds G, Stephenson E, Paul A, Sinclair N, Berretta G, Lawson C, Frey AM, Ivanova I, Adam E, Lord CJ, Cockell S, Coxhead J, Nagy N, Adams D, Szell M, Trost M, Haniffa M, Mackay SP, Perkins N, Rajan N
Publication type: Article
Publication status: Published
Journal: British Journal of Dermatology
Year: 2026
Volume: 194
Issue: 6
Pages: 1130-1141
Print publication date: 01/06/2026
Online publication date: 04/03/2026
Acceptance date: 04/02/2026
Date deposited: 01/06/2026
ISSN (print): 0007-0963
ISSN (electronic): 1365-2133
Publisher: Oxford University Press
URL: https://doi.org/10.1093/bjd/ljag044
DOI: 10.1093/bjd/ljag044
Data Access Statement: The data underlying this article will be shared on reasonable request to the corresponding author.
PubMed id: 41779628
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