Lappaconitine hydrobromide prevents NLRP3-GSDMD-mediated pyroptosis to alleviate sepsis-induced acute lung injury by enhancing NR1H3

Yuejia Lan; Qingrui Zhong; Hongkai Huang; Xiao Deng; Lu Yang; Jiayi Sun; Mingyang Liu; Xianli Meng; Jiasi Wu

doi:10.1016/j.jpha.2026.101631

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Yuejia Lan, Qingrui Zhong, Hongkai Huang, Xiao Deng, Lu Yang, Jiayi Sun, Mingyang Liu, Xianli Meng, Jiasi Wu. Lappaconitine hydrobromide prevents NLRP3-GSDMD-mediated pyroptosis to alleviate sepsis-induced acute lung injury by enhancing NR1H3[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2026.101631

Citation:

Yuejia Lan, Qingrui Zhong, Hongkai Huang, Xiao Deng, Lu Yang, Jiayi Sun, Mingyang Liu, Xianli Meng, Jiasi Wu. Lappaconitine hydrobromide prevents NLRP3-GSDMD-mediated pyroptosis to alleviate sepsis-induced acute lung injury by enhancing NR1H3[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2026.101631

Citation:

Yuejia Lan, Qingrui Zhong, Hongkai Huang, Xiao Deng, Lu Yang, Jiayi Sun, Mingyang Liu, Xianli Meng, Jiasi Wu. Lappaconitine hydrobromide prevents NLRP3-GSDMD-mediated pyroptosis to alleviate sepsis-induced acute lung injury by enhancing NR1H3[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2026.101631

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Lappaconitine hydrobromide prevents NLRP3-GSDMD-mediated pyroptosis to alleviate sepsis-induced acute lung injury by enhancing NR1H3

doi: 10.1016/j.jpha.2026.101631

Yuejia Lan^a,
Qingrui Zhong^a,
Hongkai Huang^a,
Xiao Deng^a,
Lu Yang^a,
Jiayi Sun^a,
Mingyang Liu^{b
,
,},
Xianli Meng^{a,c
,
,},
Jiasi Wu^{a,d
,
,}

a. Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China;
b. Sichuan Vocational College of Health and Rehabilitation, Meishan, Sichuan, 643000, China;
c. Institute of High Altitude Multimorbidity/TCM-Integrated High Altitude Medicine Center (Hospital of Chengdu University of TCM), Chengdu, 610075, China;
d. Key Laboratory of Acupuncture for Senile Disease (Chengdu University of TCM), Ministry of Education, Chengdu, 611137, China

Funds:

This work is supported by the National Natural Science Foundation of China (Grant NO.: 82104491), the Natural Science Foundation of Sichuan (Grant No.: 2023NSFSC0674), the Postdoctoral Science Foundation of China (Grant No.: 2021M693789), the Chengdu Municipal Health Commission's University-Commission Joint Science and Technology Innovation Fund (Grant No.: WXLH202402048), as well as “Xinglin Scholars” Subject Talent Research Promotion Program (Program No.: QJRC2023024). We thank Mingjie Chen (Shanghai NewCore Biotechnology Co., Ltd.) for providing data analysis and visualization support.

Received Date: Jul. 26, 2025
Accepted Date: Apr. 06, 2026
Rev Recd Date: Apr. 02, 2026
Available Online: Apr. 09, 2026

Abstract

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 and cecal slurry-induced SALI mouse models. In vivo and in vitro experiments revealed that LAH suppresses NLRP3 signaling activation and pyroptosis. Additionally, 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 in vitro. 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.
- Sepsis-induced acute lung injury,
- Lappaconitine hydrobromide,
- NR1H3,
- NLRP3,
- Pyroptosis

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References(49)

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