2. Academic Validation
  3. Delaying pyroptosis with an AI-screened gasdermin D pore blocker mitigates inflammatory response

Delaying pyroptosis with an AI-screened gasdermin D pore blocker mitigates inflammatory response

  • Nat Immunol. 2025 Oct;26(10):1660-1672. doi: 10.1038/s41590-025-02280-x.
Jianhui Sun # 1,  Jun Yang # 2,  Jie Tao 1,  Yifan Yang 2,  Rui Wang 1,  Huacai Zhang 1,  Wenyi Liu 1,  Shulin Zhao 1,  Runze Shao 3,  Yuhui He 3,  Shaolin Tao 4,  Yaxiong Li 2,  Hai Qu 2,  Di Liu 1,  Jingwen Li 3,  Jianxin Jiang 1,  Bo Deng 1,  Chu Gao 1,  Ping Lin 5,  Ling Zeng 6,  Ping Meng 7,  Gan Wang 8 9
Affiliations

Affiliations

  • 1 Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China.
  • 2 Key Laboratory of Cardiovascular Disease of Yunnan Province, The Affiliated Yan'an Hospital of Kunming Medical University, Kunming, China.
  • 3 China-Croatia Belt and Road Joint Laboratory on Biodiversity and Ecosystem Services, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China.
  • 4 Thoracic Surgery Department, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing, China.
  • 5 Integrative Science Center of Germplasm Creation in Western China (Chongqing) Science City, Biological Science Research Center, Southwest University, Chongqing, China.
  • 6 Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China. zengling_1025@tmmu.edu.cn.
  • 7 Key Laboratory of Cardiovascular Disease of Yunnan Province, The Affiliated Yan'an Hospital of Kunming Medical University, Kunming, China. pingmeng@yeah.net.
  • 8 Department of Trauma Medical Center, Daping Hospital, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, China. wanggan@cib.ac.cn.
  • 9 China-Croatia Belt and Road Joint Laboratory on Biodiversity and Ecosystem Services, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China. wanggan@cib.ac.cn.
  • # Contributed equally.
PMID: 40954252 DOI: 10.1038/s41590-025-02280-x
Abstract

The formation of membrane pores by cleaved N-terminal gasdermin D (GSDMD-NT) results in the release of cytokines and inflammatory cell death, known as Pyroptosis. Blocking GSDMD-NT pores is an attractive and promising strategy for mitigating inflammation. Here we demonstrate that SK56, an artificial intelligence-screened peptide, effectively obstructs GSDMD-NT pores and inhibits Pyroptosis and cytokine release in macrophages and human peripheral blood leukocyte-induced Pyroptosis. SK56 prevents septic death induced by lipopolysaccharide or cecal ligation and puncture surgery in mice. SK56 does not influence cleavage of interleukin-1β or GSDMD. Instead, SK56 inhibits the release of cytokines from pyroptotic macrophages, mitigates the activation of primary mouse dendritic cells triggered by incubation with pyroptotic cytomembranes and prevents widespread cell death of human alveolar organoids in an organoid-macrophage coculture model. SK56 blocks GSDMD-NT pores on lipid-bilayer nanoparticles and enters pyroptotic macrophages to inhibit mitochondrial damage. SK56 presents new therapeutic possibilities for counteracting inflammation, which is implicated in numerous diseases.

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