米舍利内酯直接靶向角质形成细胞膜联蛋白A2，以消除特应性皮炎中STAT3驱动的炎症和瘙痒
Micheliolide directly targets keratinocyte Annexin A2 to abrogate STAT3-driven inflammation and pruritus in atopic dermatitis.
摘要(中文译文)
对驱动和维持特应性皮炎（AD）炎症的角质形成细胞内在通路的认识有限，阻碍了靶向治疗的开发。本研究旨在鉴定AD角质形成细胞中一个新的、可成药的信号枢纽，并发现一种能够靶向该通路的天然化合物。我们对人类和小鼠AD数据集进行了无偏转录组分析。功能验证采用MC903诱导的AD小鼠模型，并进行角质形成细胞特异性基因沉默。通过天然产物库虚拟筛选鉴定候选化合物，并通过细胞热位移实验（CETSA）、分子对接和下拉实验确认直接靶点结合。通过在原代小鼠和人角质形成细胞中进行蛋白质印迹、免疫荧光和基因表达分析，获得了机制方面的见解。我们鉴定出膜联蛋白A2（ANXA2）是AD角质形成细胞中持续上调的枢纽基因。其角质形成细胞特异性沉默可有效缓解AD病理，包括炎症、瘙痒和表皮增生。在机制上，ANXA2作为STAT3磷酸化的关键上游调控因子，在AD中形成一条重要轴。虚拟筛选鉴定出天然化合物木香烃内酯（MCL）是ANXA2的直接结合物。MCL处理有效抑制了ANXA2-STAT3通路，并在体内改善了AD病理。我们的工作鉴定出ANXA2-STAT3轴是AD中一个新的致病驱动因素，并突出表明MCL是一种有前景的天然治疗药物，可靶向这一角质形成细胞内在炎症通路。
Abstract
The limited understanding of keratinocyte-intrinsic pathways that drive and sustain inflammation in atopic dermatitis (AD) has hindered the development of targeted therapies. This study aimed to identify a novel, druggable signaling hub in AD keratinocytes and to discover a natural compound capable of therapeutically targeting this pathway. We performed an unbiased transcriptomic analysis of human and murine AD datasets. Functional validation employed MC903-induced AD mouse models with keratinocyte-specific gene silencing. Candidate compounds were identified via virtual screening of natural product libraries, with direct target binding confirmed by cellular thermal shift assay (CETSA), molecular docking, and pull-down assay. Mechanistic insights were gained through western blot, immunofluorescence, and gene expression analyses in primary mouse and human keratinocytes. We identified Annexin A2 (ANXA2) as a consistently upregulated hub gene in AD keratinocytes. Its keratinocyte-specific silencing potently alleviated AD pathology, including inflammation, pruritus, and epidermal hyperplasia. Mechanistically, ANXA2 acts as an essential upstream regulator of STAT3 phosphorylation, forming a critical axis in AD. Virtual screening identified the natural compound Micheliolide (MCL) as a direct ANXA2 binder. MCL treatment effectively suppressed the ANXA2-STAT3 pathway and ameliorated AD pathology in vivo. Our work identifies the ANXA2-STAT3 axis as a novel pathogenic driver in AD and highlights MCL as a promising natural therapeutic targeting this keratinocyte-intrinsic inflammatory pathway.
如何引用
AMA
Yuqi Zhang, Ji-An Wang, Long-Fei Li, Xue-Wen Chen, Qun-Feng Gui, Cheng He, et al. Micheliolide directly targets keratinocyte Annexin A2 to abrogate STAT3-driven inflammation and pruritus in atopic dermatitis.. Phytomedicine : international journal of phytotherapy and phytopharmacology. 2026; doi:10.1016/j.phymed.2026.158303.
APA
Yuqi Zhang, Ji-An Wang, Long-Fei Li, Xue-Wen Chen, Qun-Feng Gui, Cheng He, et al (2026). Micheliolide directly targets keratinocyte Annexin A2 to abrogate STAT3-driven inflammation and pruritus in atopic dermatitis.. Phytomedicine : international journal of phytotherapy and phytopharmacology. https://doi.org/10.1016/j.phymed.2026.158303
GB/T 7714
Yuqi Zhang, Ji-An Wang, Long-Fei Li, Xue-Wen Chen, Qun-Feng Gui, Cheng He, et al. Micheliolide directly targets keratinocyte Annexin A2 to abrogate STAT3-driven inflammation and pruritus in atopic dermatitis.[J]. Phytomedicine : international journal of phytotherapy and phytopharmacology, 2026 doi:10.1016/j.phymed.2026.158303.
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