氢溴酸高乌甲素通过增强NR1H3抑制NLRP3-GSDMD介导的细胞焦亡以减轻脓毒症诱导的急性肺损伤
Lappaconitine hydrobromide prevents NLRP3-GSDMD-mediated pyroptosis to alleviate sepsis-induced acute lung injury by enhancing NR1H3.
摘要(中文译文)
有证据表明，核受体亚家族1 H组成员3（NR1H3）的激活可通过减轻炎症反应来缓解脓毒症诱导的急性肺损伤（SALI）。然而，NR1H3与炎症相互作用在应对SALI中的机制仍不清楚。此外，已报道的通过该通路改善SALI的植物化学物质有限。本研究发现，NR1H3激活可直接抑制Toll样受体4（TLR4）向脂筏的聚集，而该过程是NLR家族含pyrin结构域3（NLRP3）炎症小体启动的一部分。这一过程导致NLRP3炎症小体组装和激活受到抑制，从而减轻gasdermin-D（GSDMD）介导的细胞焦亡。此外，通过双荧光素酶报告基因检测、药物结合实验、基因表达分析和生化评价，我们确定氢溴酸高乌甲素（LAH）是一种新型NR1H3激动剂，可有效抑制TLR4-NLRP3信号通路。我们的结果表明，LAH在脂多糖（LPS）和盲肠浆液（CS）诱导的SALI小鼠模型中均可减轻炎症性肺损伤。体内和体外实验显示，LAH抑制NLRP3信号激活和细胞焦亡。此外，RNA测序（RNA-seq）和生物信息学分析表明，与白细胞介素-1β（IL-1β）产生、炎症反应调节和先天免疫反应控制相关的差异表达基因（DEGs）在LAH处理中显著富集，且DEGs中的核心基因包括NR1H3。在机制上，LAH通过调节小鼠体内NR1H3-NLRP3-GSDMD轴来减轻炎症和细胞焦亡。NR1H3的抑制进一步证实了这一发现。我们的研究为NR1H3与炎症相互作用在SALI调控中的作用提供了新视角，并表明LAH作为NR1H3激动剂通过抑制NLRP3用于SALI治疗具有治疗潜力。
Abstract
Evidence indicates that nuclear receptor subfamily 1 group H member 3 (NR1H3) activation mitigates sepsis-induced acute lung injury (SALI) by reducing inflammatory response. Nevertheless, the mechanisms underlying NR1H3-inflammation interactions in addressing SALI remain unclear. Moreover, limited phytochemicals have been documented to ameliorate SALI via this pathway. Here, we discovered that NR1H3 activation directly suppresses the clustering of toll-like receptor 4 (TLR4) to lipid rafts, which acts as a part of the priming of NLR family pyrin domain containing 3 (NLRP3) inflammasome. This process results in the suppression of NLRP3 inflammasome assembly and activation, consequently alleviating gasdermin-D (GSDMD)-mediated pyroptosis. Furthermore, through dual-luciferase reporter gene testing, drug binding assays, gene expression analysis, and biochemical evaluation, we determined lappaconitine hydrobromide (LAH) as a novel NR1H3 agonist that effectively suppresses TLR4-NLRP3 signaling pathway. Our results showed LAH attenuates inflammatory lung injury in both lipopolysaccharide (LPS) and cecal slurry (CS)-induced SALI mouse models. and experiments revealed that LAH suppresses NLRP3 signaling activation and pyroptosis. Additionally, RNA sequencing (RNA-seq) and bioinformatics analysis demonstrated that the differentially expressed genes (DEGs) linked to interleukin-1 beta (IL-1β) production, modulation of inflammatory response, and control of innate immune response were markedly enriched in LAH, and core genes amongst the DEGs included NR1H3. Mechanistically, LAH reduces inflammation and pyroptosis through modulation of NR1H3-NLRP3-GSDMD axis in mice. This finding was further substantiated by the suppression of NR1H3 . Our findings offer novel perspectives on the NR1H3-inflammation interaction in SALI regulation and indicate the therapeutic promise of LAH as an NR1H3 agonist for SALI management via NLRP3 suppression.
如何引用
AMA
Yuejia Lan, Qingrui Zhong, Hongkai Huang, Xiao Deng, Lu Yang, Jiayi Sun, et al. Lappaconitine hydrobromide prevents NLRP3-GSDMD-mediated pyroptosis to alleviate sepsis-induced acute lung injury by enhancing NR1H3.. Journal of pharmaceutical analysis. 2026; doi:10.1016/j.jpha.2026.101631.
APA
Yuejia Lan, Qingrui Zhong, Hongkai Huang, Xiao Deng, Lu Yang, Jiayi Sun, et al (2026). Lappaconitine hydrobromide prevents NLRP3-GSDMD-mediated pyroptosis to alleviate sepsis-induced acute lung injury by enhancing NR1H3.. Journal of pharmaceutical analysis. https://doi.org/10.1016/j.jpha.2026.101631
GB/T 7714
Yuejia Lan, Qingrui Zhong, Hongkai Huang, Xiao Deng, Lu Yang, Jiayi Sun, et al. Lappaconitine hydrobromide prevents NLRP3-GSDMD-mediated pyroptosis to alleviate sepsis-induced acute lung injury by enhancing NR1H3.[J]. Journal of pharmaceutical analysis, 2026 doi:10.1016/j.jpha.2026.101631.
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