天疱疮是一种严重的自身免疫性水疱性疾病，其特征是由桥粒芯糖蛋白 1 和 3 (DSG1/3) 自身抗体引发的棘层松解症。细胞凋亡在促进棘层松解中发挥着关键作用，但其确切的潜在机制仍不清楚。肿瘤坏死因子样弱凋亡诱导剂 (TWEAK) 已知可促进细胞凋亡并破坏细胞连接，但其在天疱疮发病机制中的作用仍不明确。我们的研究观察到皮损和皮损周围皮肤中 DSG1/3 表达减少，同时 TWEAK/成纤维细胞生长因子诱导型 14 (Fn14) 表达和角质形成细胞凋亡增加。体外实验表明，TWEAK 刺激的角质形成细胞表现出细胞凋亡增强、STAT1 磷酸化和细胞间 DSG1/3 表达减少。值得注意的是，批量 RNA 测序揭示了 CASPASE-3 负责介导 DSG1/3 耗竭，这通过免疫共沉淀测定中与 DSG1/3 的直接相互作用证实了这一点。纳洛酮以保持细胞粘附和防止细胞死亡而闻名，可有效减少 TWEAK 刺激的角质形成细胞中的细胞凋亡并恢复 DSG1/3 水平。纳洛酮的抗凋亡特性在小鼠天疱疮模型中得到了进一步验证。我们的研究结果阐明，TWEAK 通过增强 caspase-3 活性来促进角质形成细胞凋亡，导致天疱疮中 DSG1/3 耗竭和细胞凋亡。重要的是，纳洛酮可以对抗天疱疮发病机制中 TWEAK 诱导的细胞凋亡，提供潜在的治疗干预。版权所有 © 2024 作者。由爱思唯尔有限公司出版。保留所有权利。

Pemphigus is a severe autoimmune blistering disease characterized by acantholysis triggered by autoantibodies against desmoglein 1 and 3 (DSG1/3). Apoptosis plays a pivotal role in facilitating acantholysis, yet the precise underlying mechanism remains obscure. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is known to promote apoptosis and disrupt cell junctions, although its involvement in pemphigus pathogenesis remains ambiguous. Our study observed decreased DSG1/3 expression alongside increased TWEAK/fibroblast growth factor-inducible 14 (Fn14) expression and keratinocyte apoptosis in both lesional and perilesional skin. In vitro experiments revealed that TWEAK-stimulated keratinocytes exhibited enhanced apoptosis, STAT1 phosphorylation, and reduced intercellular DSG1/3 expression. Notably, bulk-RNA sequencing unveiled that CASPASE-3 was responsible for mediating the DSG1/3 depletion, as confirmed by direct interaction with DSG1/3 in a co-immunoprecipitation assay. Naloxone, known for preserving cellular adhesion and preventing cell death, effectively reduced apoptosis and restored DSG1/3 levels in TWEAK-stimulated keratinocytes. The anti-apoptotic properties of naloxone were further validated in a murine pemphigus model. Our findings elucidate that TWEAK facilitates keratinocyte apoptosis by augmenting caspase-3 activity, leading to DSG1/3 depletion and apoptosis in pemphigus. Importantly, naloxone can counter TWEAK-induced apoptosis in pemphigus pathogenesis, offering a potential therapeutic intervention.Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.