德国马克斯-普朗克生物化学研究所Matthias Mann、德国路德维希-马克西米利安大学Lars E. French和福建医科大学纪超研究组合作取得一项新成果。他们利用空间蛋白质组学发现JAKi可用于治疗致命皮肤病。该研究于2024年10月16日发表于国际学术期刊《自然》杂志。

据悉，中毒性表皮坏死（TEN）是一种由常见药物引发的致命性皮肤反应，是一个新出现的公共卫生问题。TEN患者的表皮会因角质细胞死亡而突然严重脱落。虽然有人揭示了诱导角质细胞死亡的分子机制，但其主要驱动因素仍不清楚，而且目前尚未发现治疗TEN的有效方法。

为了系统地绘制与TEN相关的分子变化图并确定潜在的药物靶点，研究人员采用了深度视觉蛋白质组学，该方法提供了基于单细胞、细胞类型分辨率的蛋白质组学。

研究人员分析了福尔马林固定、石蜡包埋的三种不同严重程度的，皮肤药物反应存档皮肤组织活检样本，并量化了角质形成细胞和皮肤浸润免疫细胞中含有的5000多种蛋白质。结果显示，TEN患者的免疫细胞和角质形成细胞中的I型和II型干扰素特征明显增强，磷酸化STAT1也被激活。

体外使用泛JAK抑制剂托法替尼进行靶向抑制，可降低角朊细胞定向细胞毒性。口服托法替尼、巴利替尼或JAK1特异性抑制剂阿罗西替尼或乌达替尼，可改善两种不同TEN小鼠模型的临床和组织学疾病严重程度。最重要的是，使用JAK抑制剂（JAKi）治疗是安全的，而且能使七名TEN患者的皮肤迅速重生上皮和恢复。

这项研究揭示了JAK/STAT和干扰素信号通路是TEN的关键致病因素，并证明靶向JAKi治疗TEN的潜力。

附：英文原文

Author: Nordmann, Thierry M., Anderton, Holly, Hasegawa, Akito, Schweizer, Lisa, Zhang, Peng, Stadler, Pia-Charlotte, Sinha, Ankit, Metousis, Andreas, Rosenberger, Florian A., Zwiebel, Maximilian, Satoh, Takashi K., Anzengruber, Florian, Strauss, Maximilian T., Tanzer, Maria C., Saito, Yuki, Gong, Ting, Thielert, Marvin, Kimura, Haruna, Silke, Natasha, Rodriguez, Edwin H., Restivo, Gaetana, Nguyen, Hong Ha, Gross, Annette, Feldmeyer, Laurence, Joerg, Lukas, Levesque, Mitchell P., Murray, Peter J., Ingen-Housz-Oro, Saskia, Mund, Andreas, Abe, Riichiro, Silke, John, Ji, Chao, French, Lars E., Mann, Matthias

Issue&Volume: 2024-10-16

Abstract: Toxic epidermal necrolysis (TEN) is a fatal drug-induced skin reaction triggered by common medications and is an emerging public health issue1,2,3. Patients with TEN undergo severe and sudden epidermal detachment caused by keratinocyte cell death. Although molecular mechanisms that drive keratinocyte cell death have been proposed, the main drivers remain unknown, and there is no effective therapy for TEN4,5,6. Here, to systematically map molecular changes that are associated with TEN and identify potential druggable targets, we utilized deep visual proteomics, which provides single-cell-based, cell-type-resolution proteomics7,8. We analysed formalin-fixed, paraffin-embedded archived skin tissue biopsies of three types of cutaneous drug reactions with varying severity and quantified more than 5,000 proteins in keratinocytes and skin-infiltrating immune cells. This revealed a marked enrichment of type I and type II interferon signatures in the immune cell and keratinocyte compartment of patients with TEN, as well as phosphorylated STAT1 activation. Targeted inhibition with the pan-JAK inhibitor tofacitinib in vitro reduced keratinocyte-directed cytotoxicity. In vivo oral administration of tofacitinib, baricitinib or the JAK1-specific inhibitors abrocitinib or upadacitinib ameliorated clinical and histological disease severity in two distinct mouse models of TEN. Crucially, treatment with JAK inhibitors (JAKi) was safe and associated with rapid cutaneous re-epithelialization and recovery in seven patients with TEN. This study uncovers the JAK/STAT and interferon signalling pathways as key pathogenic drivers of TEN and demonstrates the potential of targeted JAKi as a curative therapy.

DOI: 10.1038/s41586-024-08061-0

Source: https://www.nature.com/articles/s41586-024-08061-0