The gasdermin family: from pyroptosis mechanisms to therapeutic targets

IF 81.2 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Signal Transduction and Targeted Therapy Pub Date : 2026-10-02 DOI:10.1038/s41392-026-02867-2

Weilv Xu,Shiyang Liu,Zexu Yu,Jinhuang Shi,Yang Yang,Fushan Shi

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引用次数: 0

Abstract

Abstract The gasdermin (GSDM) family of proteins has emerged as the central executioner of pyroptosis, a form of inflammatory cell death characterized by plasma membrane rupture and the release of pro-inflammatory cytokines such as interleukin-1β (IL-1β), IL-18 and high mobility group protein B1 (HMGB1). Emerging evidence indicates that GSDMs exert diverse functions in health and various disease contexts, which can be either dependent on or independent of pyroptosis, including facilitating mucus secretion, regulating bone resorption, and modulating mitochondrial metabolism. This review provides a comprehensive overview of the GSDM family, detailing the molecular mechanisms of activation, regulation, pore formation, cell rupture and membrane repair. We explored the extensive crosstalk between GSDMs and other cell death modalities, including apoptosis, necroptosis, NETosis, and PANoptosis. Furthermore, we systematically discuss GSDMs’ ‘double-edged sword’ roles in diverse pathologies, ranging from host defense in infectious diseases and chronic inflammation in autoimmune disorders to their complex, context-dependent function in cancer progression and immunity. Finally, we evaluate emerging therapeutic strategies, encompassing small-molecule inhibitors such as disulfiram (DSF), necrosulfonamide (NSA) and dimethyl fumarate (DMF), as well as novel material-based delivery systems. Collectively, these advances underscore the therapeutic potential of targeting GSDMs for precise clinical intervention to treat both inflammatory and non-inflammatory diseases, as well as to enhance cancer immunotherapy.

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气皮蛋白家族：从焦亡机制到治疗靶点

gasdermin （GSDM）家族蛋白已成为焦亡的核心刽子手，焦亡是一种炎症细胞死亡形式，其特征是质膜破裂和释放促炎细胞因子，如白细胞介素-1β (IL-1β)、IL-18和高迁移率组蛋白B1 （HMGB1）。新出现的证据表明，GSDMs在健康和各种疾病环境中发挥着多种功能，这些功能可以依赖或独立于焦亡，包括促进粘液分泌、调节骨吸收和调节线粒体代谢。本文对GSDM家族进行了综述，详细介绍了GSDM家族在激活、调控、孔形成、细胞破裂和膜修复等方面的分子机制。我们探索了GSDMs与其他细胞死亡模式之间的广泛串扰，包括凋亡、坏死下垂、NETosis和PANoptosis。此外，我们系统地讨论了GSDMs在多种病理中的“双刃剑”作用，从传染病的宿主防御和自身免疫性疾病的慢性炎症，到它们在癌症进展和免疫中的复杂、环境依赖的功能。最后，我们评估了新兴的治疗策略，包括小分子抑制剂，如双硫仑（DSF）， necrosulfonamide （NSA）和富马酸二甲酯（DMF），以及新的基于材料的递送系统。总的来说，这些进展强调了靶向GSDMs的治疗潜力，可以用于精确的临床干预，治疗炎症性和非炎症性疾病，以及增强癌症免疫治疗。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Signal Transduction and Targeted Therapy Biochemistry, Genetics and Molecular Biology-Genetics

CiteScore

44.50

自引率

1.50%

发文量

384

审稿时长

5 weeks

期刊介绍： Signal Transduction and Targeted Therapy is an open access journal that focuses on timely publication of cutting-edge discoveries and advancements in basic science and clinical research related to signal transduction and targeted therapy. Scope: The journal covers research on major human diseases, including, but not limited to: Cancer,Cardiovascular diseases,Autoimmune diseases,Nervous system diseases.