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Keratinocytes lose cytoarchitectural stability and reciprocal adhesion in a process called acantholysis, which manifests as blisters and erosions. It is widely accepted that keratinocytes themselves can produce inflammatory factors such as cytokines in response to mechanical stress. This suggests that stress as induced by the binding of autoantibodies to Dsg3 might initiate similar effects in keratinocytes. In this work, we evaluate the cytokine response of human epidermal keratinocytes after treatment with anti-Dsg antibodies (AK23 and human pemphigus IgG). Quantitative gene expression (qPCR) was performed to study cytokine expression induced after AK23 treatment. Activation of the signal transducer and activation of transcription (STAT) factors and the impact of Janus kinase (JAK) inhibitors in anti-Dsg antibodies-treated keratinocytes were evaluated by Western blotting and gene expression assays. Moreover, we studied the functional role of JAK inhibitors during anti-Dsg antibody-induced cell dissociation by dispase assay. Epidermal activation of STATs in pemphigus and control skin was determined by immunohistochemistry. Finally, a pemphigus lesion in a steroid-unresponsive patient was treated with topical ruxolitinib, the clinical response and epidermal STAT activation were assessed. Our investigation revealed that loss of epidermal integrity by AK23 is accompanied by increased expression of cytokines (\n                    <jats:italic>IL6<\/jats:italic>\n                    ,\n                    <jats:italic>IL19<\/jats:italic>\n                    ,\n                    <jats:italic>IL24<\/jats:italic>\n                    ,\n                    <jats:italic>IFNE<\/jats:italic>\n                    ) and anti-Dsg antibodies activate STAT1 and STAT3. Administration of JAK inhibitors in vitro and in vivo prevented anti-Dsg antibody-induced STAT activation and cell dissociation in keratinocytes.\n                  <\/jats:p>","DOI":"10.1007\/s10753-025-02417-y","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T21:53:26Z","timestamp":1767650006000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Inhibition of the JAK\/STAT Signaling Pathway Suggests a Protective Effect against Acantholysis in Pemphigus"],"prefix":"10.1007","volume":"49","author":[{"given":"Farzan","family":"Solimani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Holstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Meier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luz Maria Cano","family":"Rochin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Mesas-Fernandez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-Fei","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria A.","family":"Feoktistova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morna F.","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amir S.","family":"Yazdi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franz Joachim","family":"Hilke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5526-7517","authenticated-orcid":false,"given":"Kamran","family":"Ghoreschi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,5]]},"reference":[{"issue":"10201","key":"2417_CR1","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1016\/S0140-6736(19)31778-7","volume":"394","author":"E Schmidt","year":"2019","unstructured":"Schmidt, E., M. Kasperkiewicz, and P. Joly. 2019. Pemphigus. Lancet 394 (10201): 882\u2013894.","journal-title":"Lancet"},{"issue":"10","key":"2417_CR2","first-page":"1188","volume":"21","author":"D Didona","year":"2023","unstructured":"Didona, D., et al. 2023. [Pemphigus- und Pemphigoid-Erkrankungen: Klinik, Diagnostik und Therapie: Pemphigus and pemphigoids: Clinical presentation, diagnosis and therapy]. Journal der Deutschen Dermatologischen Gesellschaft 21 (10): 1188\u20131211.","journal-title":"Journal der Deutschen Dermatologischen Gesellschaft"},{"issue":"20","key":"2417_CR3","doi-asserted-by":"publisher","first-page":"1189","DOI":"10.1056\/NEJM198205203062001","volume":"306","author":"GJ Anhalt","year":"1982","unstructured":"Anhalt, G. J. et al. 1982. Induction of pemphigus in neonatal mice by passive transfer of IgG from patients with the disease. 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