FP16 Targeting aberrant Janus kinase/signal transducer and activator of transcription signalling in junctional epidermolysis bullosa
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ID: 318479
2026
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Abstract
Abstract Introduction and aims Junctional epidermolysis bullosa (JEB) is a severe, genetic disorder causing extreme skin fragility, blistering, and aberrant granulation tissue formation and inflammation owing to defects in basement membrane proteins such as laminin-332. Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling plays a critical role for a wide range of cytokines and growth factors controlling skin homeostasis and inflammation. Dysregulation of the JAK/STAT pathway and its therapeutic potential have been investigated in other skin diseases including atopic dermatitis and epidermolysis bullosa pruriginosa, but not in JEB, which is the focus of this project. Methods Using our JEB in vitro disease models, we investigated JAK/STAT signalling activation upon LAMA3 depletion. We then screened different classes of JAK/STAT inhibitors for their potential to suppressing aberrant JAK/STAT signalling and improving the JEB phenotype by combining immunohistochemistry, enzyme-linked immunosorbent assay and Western blot analysis. The most effective JAK/STAT inhibitor was further tested in our preclinical JEB in vivo disease model and changes to the JEB phenotype were assessed by histology. Results Depletion of LAMA3 in keratinocytes leads to an increase in JAK/STAT signalling activity in our JEB disease models. Treatment with different JAK/STAT inhibitors, revealed that selective JAK1 inhibition significantly decreased STAT3 phosphorylation in a concentration-dependent manner. Our inducible JEB in vivo disease model shows prominent JAK/STAT signalling activation in the interfollicular epidermis, in particular in blistered skin areas increasing with disease severity. Treatment with selected JAK1 inhibitor not only decreased aberrant STAT3 phosphorylation, inflammation, cell proliferation and granulation tissue formation, but also improved overall mouse health and skin regeneration. Conclusions Collectively, our study revealed that JAK/STAT signalling is deregulated in keratinocytes upon LAMA3 depletion that can be efficiently normalized by treatment with a selective JAK1 inhibitor. Inhibition of the pathological JAK/STAT signalling in vivo significantly improved skin health and regeneration in JEB.
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| Authors | Mohammad R A Khan, E Rognoni, M P Caley |
| Journal | the british journal of dermatology |
| Year | 2026 |
| DOI |
10.1093/bjd/ljag151.039
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| URL | |
| Keywords | Keywords not found |
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