{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T18:25:41Z","timestamp":1779215141132,"version":"3.51.4"},"reference-count":45,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T00:00:00Z","timestamp":1771372800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T00:00:00Z","timestamp":1771372800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Biochem &amp;amp; Molecular Tox"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Rapid and extensive epithelial cell death in skin and mucous membranes is the hallmark of Toxic epidermal necrolysis (TEN). High levels of TNF\u2010\u03b1 and IFN\u2010\u03b3 have been detected in the blister fluids of skin lesions in TEN patients. Available literature shows that TNF\u2010\u03b1 synergy with IFN\u2010\u03b3 (TNF\u2010\u03b1\/IFN\u2010\u03b3) elicited cell death in diverse cells. Thus, the cytotoxic effect and underlying mechanism of TNF\u2010\u03b1 and IFN\u2010\u03b3 on HaCaT cells were investigated. Confluent HaCaT cells were subjected to serial doses of either TNF\u2010\u03b1 alone, IFN\u2010\u03b3 alone, or combination TNF\u2010\u03b1 with IFN\u2010\u03b3 (TNF\u2010\u03b1\/IFN\u2010\u03b3) for indicated time intervals. The cytotoxicity were then evaluated by morphologic change and trypan blue exclusion assay. The mechanism involving in TNF\u2010\u03b1 and IFN\u2010\u03b3\u2010elicited HaCaT cell death were examined through the change expression of c\u2010GSDM\u2010E, c\u2010Caspase\u20103, p\u2010MLKL expression by western blot. TNF\u2010\u03b1\/IFN\u2010\u03b3 significantly induced HaCaT cell death and showed a dose\u2010 and time\u2010dependent manner. However, TNF\u2010\u03b1 alone or IFN\u2010\u03b3 alone failed to do it. Western blot analysis confirmed that TNF\u2010\u03b1\/IFN\u2010\u03b3 triggers HaCaT cell death through PANoptosis, as evidenced by increased expression levels of c\u2010GSDMD, c\u2010GSDME, c\u2010Caspase\u20103, and phospho\u2010MLKL (pMLKL). High level of TNF\u2010\u03b1 and IFN\u2010\u03b3 are the main cause to induce epithelial cell death of skin in TEN. These suggest that drugs with the potential to inhibit TNF\u2010\u03b1 and IFN\u2010\u03b3 expression and downstream signaling could be developed as treatments for TEN in the future.<\/jats:p>","DOI":"10.1002\/jbt.70751","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T07:07:32Z","timestamp":1771484852000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Molecular Insights Into TNF\u2010\u03b1 and IFN\u2010\u03b3\u2010Induced Epithelial Cell Death in Toxic Epidermal Necrolysis"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9991-3835","authenticated-orcid":false,"given":"Jia\u2010Ning","family":"Syu","sequence":"first","affiliation":[{"name":"Experimental Animal Center, Department of Molecular Biology and Cell Research Chang Bing Show Chwan Memorial Hospital  Changhua Taiwan, 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