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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

Acta Pharmacologica Sinica volume 46, pages 2734–2750 (2025)Cite this article

Abstract

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 mg·kg–1·d–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.

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Fig. 1: ZQS5029-1 ameliorated NASH in an HFD + CCl4 induced murine model.
Fig. 2: ZQS5029-1 exhibited therapeutic effect in ob/ob-GAN induced NASH mice.
Fig. 3: ZQS5029-1 inhibited hepatic NLRP3 inflammasome activation in murine NASH models.
Fig. 4: ZQS5029-1 inhibited the activation and assembly of NLRP3 inflammasome in macrophages.
Fig. 5: ZQS5029-1 blocked NLRP3 inflammasome activation in HSCs and downregulated the expression of fibrotic markers.
Fig. 6: ZQS5029-1 protected against the macrophage NLRP3 inflammasome activation-elicited cell injury, death, and lipid accumulation in primary hepatocytes and HSC activation.
Fig. 7: ZQS5029-1 directly bound to caspase-1.
Fig. 8: H236 mutation of Caspase-1 eliminated the protective effects of ZQS5029-1 on NLRP3 inflammasome activation-elicited injury, death, and lipid accumulation in hepatocytes and HSC activation.
Fig. 9: ZQS5029-1 suppresses NLRP3 inflammasome activation by targeting Caspase-1 and alleviates non-alcoholic steatohepatitis in mice.

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Acknowledgements

This study was supported by State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (Grant No. SKLDR-2022-LH-08).

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  1. These authors contributed equally: Ling-yan Xia, Nai-rong Yu.

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  1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Ling-yan Xia, Su-ling Huang, Hui Qu, Li Qin & Ying Leng

  2. University of Chinese Academy of Sciences, Beijing, 100049, China

    Ling-yan Xia, Nai-rong Yu, Qin-shi Zhao & Ying Leng

  3. State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China

    Nai-rong Yu & Qin-shi Zhao

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YL, QSZ, and LYX designed the research. LYX, NRY, SLH, HQ, and LQ performed the research. LYX and NRY analyzed and interpreted the data. YL, QSZ, LYX, and NRY wrote the paper. All authors approved the final version of the manuscript.

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Xia, Ly., Yu, Nr., Huang, Sl. 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 Pharmacol Sin 46, 2734–2750 (2025). https://doi.org/10.1038/s41401-025-01569-9

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