Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, Hong Kong SAR, China.
Department of Endocrinology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Front Immunol. 2024 Aug 26;15:1456244. doi: 10.3389/fimmu.2024.1456244. eCollection 2024.
Inflammatory diseases compromise a clinically common and diverse group of conditions, causing detrimental effects on body functions. Gasdermins (GSDM) are pore-forming proteins, playing pivotal roles in modulating inflammation. Belonging to the GSDM family, gasdermin D (GSDMD) actively mediates the pathogenesis of inflammatory diseases by mechanistically regulating different forms of cell death, particularly pyroptosis, and cytokine release, in an inflammasome-dependent manner. Aberrant activation of GSDMD in different types of cells, such as immune cells, cardiovascular cells, pancreatic cells and hepatocytes, critically contributes to the persistent inflammation in different tissues and organs. The contributory role of GSDMD has been implicated in diabetes mellitus, liver diseases, cardiovascular diseases, neurodegenerative diseases, and inflammatory bowel disease (IBD). Clinically, alterations in GSDMD levels are potentially indicative to the occurrence and severity of diseases. GSDMD inhibition might represent an attractive therapeutic direction to counteract the progression of inflammatory diseases, whereas a number of GSDMD inhibitors have been shown to restrain GSDMD-mediated pyroptosis through different mechanisms. This review discusses the current understanding and future perspectives on the role of GSDMD in the development of inflammatory diseases, as well as the clinical insights of GSDMD alterations, and therapeutic potential of GSDMD inhibitors against inflammatory diseases. Further investigation on the comprehensive role of GSDM shall deepen our understanding towards inflammation, opening up more diagnostic and therapeutic opportunities against inflammatory diseases.
炎症性疾病是一组临床上常见且多样化的疾病，对身体功能造成有害影响。Gasdermins（GSDM）是一种形成孔的蛋白质，在调节炎症方面发挥着关键作用。属于 GSDM 家族的 GSDMD 通过以炎症小体依赖的方式机械调节不同形式的细胞死亡，特别是细胞焦亡和细胞因子释放，积极介导炎症性疾病的发病机制。GSDMD 在不同类型的细胞（如免疫细胞、心血管细胞、胰腺细胞和肝细胞）中的异常激活，对不同组织和器官中的持续炎症有重要贡献。GSDMD 在糖尿病、肝病、心血管疾病、神经退行性疾病和炎症性肠病（IBD）中的作用已被证实。临床上，GSDMD 水平的改变可能与疾病的发生和严重程度有关。抑制 GSDMD 可能代表了对抗炎症性疾病进展的有吸引力的治疗方向，而许多 GSDMD 抑制剂已被证明通过不同的机制抑制 GSDMD 介导的细胞焦亡。本综述讨论了 GSDMD 在炎症性疾病发展中的作用及其临床意义，以及 GSDMD 改变的治疗潜力和针对炎症性疾病的 GSDMD 抑制剂的治疗潜力。对 GSDM 全面作用的进一步研究将加深我们对炎症的理解，为炎症性疾病的诊断和治疗提供更多机会。
