Shi Si, Zheng Ruihan, Luo Li, Xia Binbin, Yang Zexin, Lin Wante, Mei Yiling, Fan Xiaoxi, Huang Zhouqing, Huang Weijian, Ye Bozhi, Dai Shanshan
Department of Geriatric Medicine, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang, People's Republic of China; The First Clinical Medical College, Wenzhou Medical University, Zhejiang, People's Republic of China.
The Key Laboratory of Cardiovascular Disease of Wenzhou, Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang, People's Republic of China.
Eur J Pharmacol. 2025 Sep 15;1003:178006. doi: 10.1016/j.ejphar.2025.178006. Epub 2025 Jul 26.
Sepsis-induced myocardial dysfunction is a life-threatening complication with significant implications for clinical outcomes in critically ill patients. Emerging evidence indicates that the pharmacological targeting of Gasdermin D (GSDMD)-mediated pyroptosis represents a novel therapeutic approach for septic myocardial dysfunction. The GSDMD inhibitor Y1 (GI-Y1), a new small-molecule inhibitor developed through structure-based virtual screening against the GSDMD-N terminal domain, demonstrates selective binding affinity and potent inhibitory activity as shown in preliminary screening assays. Our systematic evaluation revealed that GI-Y1 significantly improved cardiac function and reduced myocardial injury in septic mice induced by lipopolysaccharide (LPS) and cecal ligation and puncture (CLP). GI-Y1 effectively inhibited GSDMD-mediated pyroptosis both in vivo and in vitro. Importantly, genetic validation experiments conducted using GSDMD-knockout (Gsdmd) mice and siRNA-mediated knockdown of GSDMD in cardiomyocytes demonstrated a complete abrogation of GI-Y1's therapeutic effects, confirming that the cardioprotective efficacy of GI-Y1 against septic cardiac dysfunction relies on GSDMD. Notably, macrophage membrane-coated GI-Y1 nanoparticles (GI-Y1@MM-NPs) exhibited enhanced therapeutic efficacy in alleviating inflammation and cardiac dysfunction in septic mice when compared to free GI-Y1. Collectively, these findings indicate that GI-Y1 exerts protective effects on sepsis-related cardiac dysfunction by targeting GSDMD and inhibiting its mediated pyroptosis. GI-Y1 and GI-Y1@MM-NPs may serve as effective therapeutic strategies for treating sepsis-induced myocardial dysfunction.
脓毒症诱导的心肌功能障碍是一种危及生命的并发症，对危重症患者的临床结局具有重大影响。新出现的证据表明，针对Gasdermin D（GSDMD）介导的细胞焦亡进行药物靶向治疗是脓毒症性心肌功能障碍的一种新的治疗方法。GSDMD抑制剂Y1（GI-Y1）是一种通过基于结构的虚拟筛选针对GSDMD-N末端结构域开发的新型小分子抑制剂，如初步筛选试验所示，它具有选择性结合亲和力和强大的抑制活性。我们的系统评估显示，GI-Y1显著改善了脂多糖（LPS）和盲肠结扎穿刺（CLP）诱导的脓毒症小鼠的心脏功能，并减轻了心肌损伤。GI-Y1在体内和体外均有效抑制GSDMD介导的细胞焦亡。重要的是，使用GSDMD基因敲除（Gsdmd）小鼠进行的基因验证实验以及在心肌细胞中通过小干扰RNA（siRNA）介导的GSDMD敲低实验表明，GI-Y1的治疗效果完全消失，证实了GI-Y1对脓毒症性心脏功能障碍的心脏保护作用依赖于GSDMD。值得注意的是，与游离的GI-Y1相比，巨噬细胞膜包被的GI-Y1纳米颗粒（GI-Y1@MM-NPs）在减轻脓毒症小鼠的炎症和心脏功能障碍方面表现出更强的治疗效果。总的来说，这些发现表明，GI-Y1通过靶向GSDMD并抑制其介导的细胞焦亡，对脓毒症相关的心脏功能障碍发挥保护作用。GI-Y1和GI-Y1@MM-NPs可能是治疗脓毒症诱导的心肌功能障碍的有效治疗策略。
