Pan-membrane pyroptosis of liver induced by gasdermin-encoding mRNAs
Gasdermin (GSDM)-mediated pyroptosis has been extensively visualized <i>in vitro</i> and linked to multiple physiological and pathological processes. However, the <i>in vivo</i> phenotype and clinical outcome of pyroptosis remain undetermined. Here, we sought to profile <i>in vivo</i> pyroptosis using lipid-nanoparticle (LNP)-encapsulated mRNA encoding the pore-forming N-terminal of GSDMD (GSDMD<sup>NT</sup>). Upon intravenous (IV) injection, robust expression of GSDMD<sup>NT</sup> 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 GSDMD<sup>NT</sup> 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 <i>in vitro</i> and <i>in vivo</i>, 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.
Authors
- Byung‐Ho Kang (ORCID: https://orcid.org/0000-0002-4299-2170)
- Guan Yang (ORCID: https://orcid.org/0000-0002-4026-6976)
- Xing‐Yao Huang (ORCID: https://orcid.org/0000-0002-3917-8100)
- Qin Wang (ORCID: https://orcid.org/0000-0001-7759-0238)
- Zhiwei Lin (ORCID: https://orcid.org/0000-0002-9772-486X)
- Xuedong Zhou (ORCID: https://orcid.org/0000-0002-9319-7302)
- Cheng‐Feng Qin (ORCID: https://orcid.org/0000-0002-0632-2807)
- Kaiyan Zhang
- Qing Ye (ORCID: https://orcid.org/0000-0002-6756-0630)
- Kai Li (ORCID: https://orcid.org/0000-0002-1746-7913)
- Xiaoyan Wu (ORCID: https://orcid.org/0009-0000-2846-1800)
- Xiang Chen (ORCID: https://orcid.org/0000-0002-5045-9253)
- Li Lin (ORCID: https://orcid.org/0000-0001-9024-4014)
- Lu Lv
- Jie Xu (ORCID: https://orcid.org/0000-0002-9173-977X)
- Xiuli Yan (ORCID: https://orcid.org/0000-0002-9228-0032)
- Hua Lin (ORCID: https://orcid.org/0000-0002-7390-4559)
- Yucai Wang (ORCID: https://orcid.org/0000-0002-1576-8341)
- Wenlong Ma (ORCID: https://orcid.org/0000-0001-5102-9151)
- Bo Ying (ORCID: https://orcid.org/0009-0000-3453-1836)
- Jia Zhou (ORCID: https://orcid.org/0000-0003-1516-123X)
- Xia Zhong
- Yi-Jiao Huang (ORCID: https://orcid.org/0009-0000-7966-9767)
Institutions
- University of Science and Technology of China (CN)
- Beijing University of Chinese Medicine (CN)
- Chinese University of Hong Kong (HK)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Academy of Military Medical Sciences (CN)
- Suzhou Research Institute (CN)
- Beijing Proteome Research Center (CN)
- Tsinghua University (CN)
Publication Details
- Journal
- National Science Review
- Published
- 2025-10-21
- DOI
- https://doi.org/10.1093/nsr/nwaf452
- Citations
- 1
- Primary Topic
- Inflammasome and immune disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- National Natural Science Foundation of China
- State Key Laboratory of Pathogen and Biosecurity
- National Key Research and Development Program of China