Activation of gasdermin D (GSDMD) and its concomitant cardiomyocyte pyroptosis are critically involved in multiple cardiac pathological conditions. Pharmacological inhibition or gene knockout of GSDMD could protect cardiomyocyte from pyroptosis and dysfunction. Thus, seeking and developing highly potent GSDMD inhibitors probably provide an attractive strategy for treating diseases targeting GSDMD. Through structure-based virtual screening, pharmacological screening and subsequent pharmacological validations, we preliminarily identified GSDMD inhibitor Y1 (GI-Y1) as a selective GSDMD inhibitor with cardioprotective effects. Mechanistically, GI-Y1 binds to GSDMD and inhibits lipid- binding and pyroptotic pore formation of GSDMD-N by targeting the Arg7 residue. Importantly, we confirmed the cardioprotective effect of GI-Y1 on myocardial I/R injury and cardiac remodeling by targeting GSDMD. More extensively, GI-Y1 also inhibited the mitochondrial binding of GSDMD-N and its concomitant mitochondrial dysfunction. The findings of this study identified a new drug (GI-Y1) for the treatment of cardiac disorders by targeting GSDMD, and provide a new tool compound for pyroptosis research.

Gasdermin D (GSDMD) 的激活及其伴随的心肌细胞焦亡与多种心脏病理状况密切相关。 GSDMD的药理抑制或基因敲除可以保护心肌细胞免于焦亡和功能障碍。因此，寻找和开发高效的 GSDMD 抑制剂可能为治疗针对 GSDMD 的疾病提供有吸引力的策略。通过基于结构的虚拟筛选、药理筛选和后续药理验证，我们初步鉴定GSDMD抑制剂Y1（GI-Y1）是一种具有心脏保护作用的选择性GSDMD抑制剂。从机制上讲，GI-Y1 与 GSDMD 结合，并通过靶向 Arg7 残基抑制 GSDMD-N 的脂质结合和焦亡孔形成。重要的是，我们通过靶向GSDMD证实了GI-Y1对心肌I/R损伤和心脏重塑的心脏保护作用。更广泛地说，GI-Y1 还抑制 GSDMD-N 的线粒体结合及其伴随的线粒体功能障碍。该研究结果确定了一种靶向GSDMD治疗心脏疾病的新药（GI-Y1），并为细胞焦亡研究提供了新的工具化合物。