Ning Changwen, Gao Fenghua, Wang Zhe, An Huaying, Liu Pengyu, Sun Yanan, Li Ru, Song Zhuyang, Yuan Yuanyuan, Li Jinlong, Ma Jun, Jiang Xingwei, Yu Qun
Institute of Health Service and Transfusion Medicine, Academy of Military Medical Sciences, Beijing, China.
PLoS One. 2025 Aug 4;20(8):e0328522. doi: 10.1371/journal.pone.0328522. eCollection 2025.
The NOD-like receptor protein (NLRP)3 inflammasome plays a critical role in acute respiratory distress syndrome (ARDS) by activating caspase-1, which cleaves the precursor forms of IL-1β and IL-18 into active cytokines and induces pyroptosis by cleaving gasdermin D (GSDMD). LBH589, a pan-histone deacetylase inhibitor, exhibits promising anti-inflammatory and immunomodulatory properties. However, the protective effect and underlying mechanism of LBH589 against ARDS is still unclear. In this study, we aim to determine whether and how LBH589 inhibits NLRP3 inflammasome activation while exerting its anti-inflammatory effect. Our data demonstrated that LBH589 effectively suppressed NLRP3 inflammasome activation in lipopolysaccharides (LPS)-primed and adenosine triphosphate (ATP)-stimulated J774A.1 cells and bone marrow-derived macrophages (BMDMs), evidenced by attenuated cleaved caspase-1 and IL-1β, IL-18, IL-16 release, as along with reduced GSDMD-mediated pyroptosis and ASC speck formation. Additionally, LBH589 significantly decreased mitochondrial reactive oxygen species (mtROS) and oxidized mitochondrial DNA (Ox-mtDNA), key triggers of inflammasome activation. Importantly, both prophylactic and therapeutic administration of LBH589 inhibited the pro-inflammatory cytokines secretion in lung tissue and ameliorated lipopolysaccharide (LPS)-induced ARDS in mice. These findings suggest that LBH589 may provide therapeutic benefits in ARDS by attenuating NLRP3 inflammasome activation and pyroptosis.
核苷酸结合寡聚化结构域样受体蛋白（NLRP）3炎性小体通过激活半胱天冬酶-1在急性呼吸窘迫综合征（ARDS）中起关键作用，半胱天冬酶-1将白细胞介素-1β（IL-1β）和白细胞介素-18（IL-18）的前体形式切割成活性细胞因子，并通过切割gasdermin D（GSDMD）诱导细胞焦亡。LBH589是一种泛组蛋白去乙酰化酶抑制剂，具有良好的抗炎和免疫调节特性。然而，LBH589对ARDS的保护作用及其潜在机制仍不清楚。在本研究中，我们旨在确定LBH589是否以及如何抑制NLRP3炎性小体的激活，同时发挥其抗炎作用。我们的数据表明，LBH589有效抑制脂多糖（LPS）预处理和三磷酸腺苷（ATP）刺激的J774A.1细胞和骨髓来源的巨噬细胞（BMDM）中NLRP3炎性小体的激活，这表现为半胱天冬酶-1、IL-1β、IL-18、IL-16的切割产物释放减少，以及GSDMD介导的细胞焦亡和凋亡相关斑点样蛋白（ASC）斑点形成减少。此外，LBH589显著降低了线粒体活性氧（mtROS）和氧化型线粒体DNA（Ox-mtDNA），这两者是炎性小体激活的关键触发因素。重要的是，LBH589的预防性和治疗性给药均抑制了肺组织中促炎细胞因子的分泌，并改善了脂多糖（LPS）诱导的小鼠急性呼吸窘迫综合征。这些发现表明，LBH589可能通过减弱NLRP3炎性小体的激活和细胞焦亡，为急性呼吸窘迫综合征提供治疗益处。
