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Jargosch, M. ; Wasserer, S.* ; Eigemann, J.* ; Raunegger, T.* ; Kurzen, N.* ; Ding-Pfennigdorff, D.* ; Bartnik, E.* ; Schmidt-Weber, C.B. ; Biedermann, T.* ; Eyerich, S. ; Eyerich, K.* ; Florian, P.* ; Herrmann, M.* ; Saas, J.* ; Lauffer, F.*

Inhibition of RIPK1 prevents keratinocyte cell death and reduces skin inflammation in type 1 mediated chronic inflammatory skin diseases.

J. Allergy Clin. Immunol., DOI: 10.1016/j.jaci.2026.02.006 (2026)
Postprint Research data DOI PMC
Open Access Hybrid
BACKGROUND: Type 1 mediated chronic inflammatory skin diseases (ISD) affect skin, hair, nails and mucosa and dramatically impact patient's quality of life. The two most prominent examples are lichen planus (LP) and cutaneous lupus erythematosus (CLE). Various cell death pathways are activated in both diseases, including apoptosis and necroptosis. RIPK1 is a key regulator of programmed cell death and thus represents a potential new target for the treatment of these diseases. OBJECTIVE: To determine the impact of RIPK1 on cell death and inflammation in LP and CLE. METHODS: RNA-sequencing of ISD (n=179). Assessing cell death, hypothermia and inflammatory markers affected by Eclitasertib, a novel RIPK1 inhibitor, in human cells, murine TNF-α induced systemic inflammatory response syndrome (SIRS) model, reconstructed human epidermis and ex vivo skin biopsy culture. RESULTS: Markers of apoptosis (Caspase 8) and necroptosis (RIPK3, MLKL) are upregulated in LP and CLE. Eclitasertib restored body temperature when orally administered 15 minutes after TNF-α injection in murine SIRS model. Further, RIPK1 inhibition prevented keratinocyte cell death, normalized epidermal architecture and decreased the release of IL-1α, IL-1β, TNF-α, and CCL20 in reconstructed human epidermis upon stimulation with LP/CLE T cell supernatant. Ex vivo culture of LP and CLE biopsies with Eclitasertib reduced expression of disease specific genes and downregulated pathways associated to inflammation. CONCLUSION: Inhibition of RIPK1 targets two major pathogenic events in LP and CLE: epidermal cell death and type 1 mediated skin inflammation.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Eclitasertib ; Lichen Planus ; Ripk1 ; Cell Death ; Cutaneous Lupus Erythematosus ; Necroptosis ; Targeted Therapy
ISSN (print) / ISBN 0091-6749
e-ISSN 1097-6825
Journal The journal of allergy and clinical immunology
Publisher Elsevier
Publishing Place Amsterdam [u.a.]
Reviewing status Peer reviewed
Institute(s) Institute for Allergy Research (IAF)