陆军医科大学曾灵团队的最新研究揭示了通过人工智能筛选的gasdermin D孔道阻断剂延缓细胞焦亡可减轻炎症反应。2025年9月15日出版的《自然—免疫学》发表了这项成果。

在这里，课题组证明了人工智能筛选的肽SK56可以有效地阻断GSDMD-NT孔，抑制巨噬细胞和人外周血白细胞诱导的焦亡和细胞因子释放。SK56可预防脂多糖或盲肠结扎和穿刺手术引起的小鼠脓毒性死亡。SK56不影响白细胞介素-1β或GSDMD的切割。相反，在类器官-巨噬细胞共培养模型中，SK56抑制热噬巨噬细胞细胞因子的释放，减轻由热噬细胞膜孵养引发的原代小鼠树突状细胞的激活，并防止人肺泡类器官的广泛细胞死亡。SK56阻断脂质双层纳米颗粒上的GSDMD-NT孔，进入热噬细胞，抑制线粒体损伤。SK56为对抗炎症提供了新的治疗可能性，炎症与许多疾病有关。

据了解，经切割的gasdermin D氨基末端片段（GSDMD-NT）形成膜孔，导致细胞因子的释放和炎症细胞死亡，称为焦亡。阻断GSDMD-NT毛孔是一种有吸引力和有前途的减轻炎症的策略。

附：英文原文

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

Author: Sun, Jianhui, Yang, Jun, Tao, Jie, Yang, Yifan, Wang, Rui, Zhang, Huacai, Liu, Wenyi, Zhao, Shulin, Shao, Runze, He, Yuhui, Tao, Shaolin, Li, Yaxiong, Qu, Hai, Liu, Di, Li, Jingwen, Jiang, Jianxin, Deng, Bo, Gao, Chu, Lin, Ping, Zeng, Ling, Meng, Ping, Wang, Gan

Issue&Volume: 2025-09-15

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.

DOI: 10.1038/s41590-025-02280-x

Source: https://www.nature.com/articles/s41590-025-02280-x