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Dehydrotrametenolic acid methyl ester, a triterpenoid of Poria cocos, alleviates non-alcoholic steatohepatitis by suppressing NLRP3 inflammasome activation via targeting Caspase-1 in mice

文献类型：期刊论文

作者Xia, Ling-yan2,3; Yu, Nai-rong1,2; Huang, Su-ling3; Qu, Hui3; Qin, Li3; Zhao, Qin-shi1,2; Leng, Ying2,3
刊名ACTA PHARMACOLOGICA SINICA
出版日期2025-05-06
页码17
关键词non-alcoholic steatohepatitis dehydrotrametenolic acid methyl ester NLRP3 inflammasome caspase-1 macrophage-hepatocyte/HSC crosstalk
ISSN号1671-4083
DOI10.1038/s41401-025-01569-9
英文摘要Non-alcoholic steatohepatitis (NASH) has emerged as a prevalent chronic liver disease with a huge unmet clinical need. A few studies have reported the beneficial effects of Poria cocos Wolf (P. cocos) extract on NASH mice, but the active components were still unknown. In this study we investigated the therapeutic effects of dehydrotrametenolic acid methyl ester (ZQS5029-1), a lanosterol-7,9(11)-diene triterpenes in P. cocos, in a high-fat diet plus CCl4 induced murine NASH model and a GAN diet induced ob/ob murine NASH model. The NASH mice were treated with ZQS5029-1 (75 mgkg-1d-1, i.g.) for 6 and 8 weeks, respectively. We showed that ZQS5029-1 treatment markedly relieved liver injury, inflammation and fibrosis in both the murine NASH models. We found that ZQS5029-1 treatment significantly suppressed hepatic NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation in both the NASH murine models, and blocked lipopolysaccharides (LPS)+adenosine 5'-triphosphate (ATP)/Nigericin-induced NLRP3 inflammasome activation in bone marrow-derived macrophages (BMDMs) and Kupffer cells in vitro. We demonstrated that ZQS5029-1 directly bound to the H236 residue of mouse Caspase-1, thereby inhibiting NLRP3 inflammasome activation. The effects of ZQS5029-1 on macrophage-hepatocyte/HSC crosstalk were analyzed using the supernatants from macrophages preconditioned with LPS + ATP introduced into hepatocytes and hepatic stellate cells (HSCs). We found that the conditioned medium from the BMDMs induced injury and death, as well as lipid accumulation in hepatocytes, and activation of HSCs; these effects were blocked by conditioned medium from BMDMs treated with ZQS5029-1. Moreover, the protective effects of ZQS5029-1 on hepatocytes and HSCs were eliminated by H236A-mutation of Caspase-1. We conclude that ZQS5029-1 is a promising lead compound for the treatment of NASH by inhibiting NLRP3 inflammasome activation through targeting Caspase-1 and regulating the macrophage-hepatocyte/HSC crosstalk.
WOS关键词LIVER-INJURY ; FATTY LIVER ; FIBROSIS ; CELLS ; DIET ; MACROPHAGES ; CONTRIBUTE ; MECHANISM ; RELEASE ; NASH
资助项目State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SKLDR-2022-LH-08]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001482177100001
出版者NATURE PUBL GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/317587]  
专题新药研究国家重点实验室
通讯作者Zhao, Qin-shi; Leng, Ying
作者单位1.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources West Chi, Kunming 650201, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Xia, Ling-yan,Yu, Nai-rong,Huang, Su-ling,et al. Dehydrotrametenolic acid methyl ester, a triterpenoid of Poria cocos, alleviates non-alcoholic steatohepatitis by suppressing NLRP3 inflammasome activation via targeting Caspase-1 in mice[J]. ACTA PHARMACOLOGICA SINICA,2025:17.
APA Xia, Ling-yan.,Yu, Nai-rong.,Huang, Su-ling.,Qu, Hui.,Qin, Li.,...&Leng, Ying.(2025).Dehydrotrametenolic acid methyl ester, a triterpenoid of Poria cocos, alleviates non-alcoholic steatohepatitis by suppressing NLRP3 inflammasome activation via targeting Caspase-1 in mice.ACTA PHARMACOLOGICA SINICA,17.
MLA Xia, Ling-yan,et al."Dehydrotrametenolic acid methyl ester, a triterpenoid of Poria cocos, alleviates non-alcoholic steatohepatitis by suppressing NLRP3 inflammasome activation via targeting Caspase-1 in mice".ACTA PHARMACOLOGICA SINICA (2025):17.

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来源：上海药物研究所

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