Pan-membrane pyroptosis of liver induced by gasdermin-encoding mRNAs

作者：Yi-Jiao Huang, Li Lin, Guan Yang, Wenlong Ma, Qin Wang, Xiuli Yan, Qing Ye, Xing‐Yao Huang, Kai Li, Lu Lv, Xiaoyan Wu, Kaiyan Zhang, Jia Zhou, Xiang Chen, Hui-Sang Lin, Jie Xu, Xue-Tao Zhou, Zhuang-Ran Lin, Xia Zhong, Bo Ying, Yucai Wang, Byung‐Ho Kang, Cheng‐Feng Qin · 发表于：National Science Review · 年份：2025 · DOI：10.1093/nsr/nwaf452 · 被引用次数：3 · 研究领域：Inflammasome and immune disorders、Streptococcal Infections and Treatments、Gout, Hyperuricemia, Uric Acid

ABSTRACT Gasdermin (GSDM)-mediated pyroptosis has been extensively visualized in vitro and linked to multiple physiological and pathological processes. However, the in vivo phenotype and clinical outcome of pyroptosis remain undetermined. Here, we sought to profile in vivo pyroptosis using lipid-nanoparticle (LNP)-encapsulated mRNA encoding the pore-forming N-terminal of GSDMD (GSDMDNT). Upon intravenous (IV) injection, robust expression of GSDMDNT led to acute liver damage, systemic inflammation and sudden death, both in mice and non-human primates, which could be reversed by the GSDMD inhibitor disulfiram or glucocorticoids. Imaging techniques revealed that GSDMDNT targeted both plasma membrane and intracellular membranous organelles, causing membrane rupture and organelle swelling, as well as the formation of intracellular membranous vacuoles. Furthermore, heterologous expression of other GSDM members also caused pyroptosis, both in vitro and in vivo, with varying magnitude. These findings provide insights into the dynamic characteristics of pyroptotic organ injury-related diseases and offer the basis for developing GSDM-based therapeutics.