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Oridonin exerts dual therapeutic effects in MASLD mice by integrating lipid homeostasis and drug bioactivation via the LXRα–CES1/CES2 pathway

Acta Pharmacologica Sinica (2026)Cite this article

Abstract

Carboxylesterases CES1 and CES2 are the pivotal hepatic enzymes involved in triglyceride (TG) hydrolysis and prodrug metabolism, yet their expression and activity are suppressed in metabolic dysfunction-associated steatotic liver disease (MASLD). Liver X receptor alpha (LXRα) is known to play a crucial role in maintaining the constitutive expression of CES1 in human liver cells. Oridonin (ORI) is a diterpene derived from a traditional Chinese herb that possesses antitumor, anti-inflammatory, and antimicrobial activities. We previously demonstrated that ORI, as a natural LXRα agonist, activated the LXRα-ATGL/EPT1 pathway, correcting the TG/phosphatidylethanolamine (PE) lipid imbalance induced by obesity and thereby improving MASLD. Here, we investigated the regulatory role of LXRα on CES1/CES2 expression in MASLD liver and elucidated the underlying molecular mechanisms of ORI’s lipid-lowering effects. A high-fat diet (HFD)-induced steatosis model was established in mice. The mice were treated with ORI (100 mg·kg−1·d−1, i.g.) from the 16th to the 24th week. RNA-seq analysis in MASLD patients demonstrated that LXRα is a key transcriptional regulator of CES1 and CES2. LXRα knockout (LXRα−/−) mice exhibited aggravated HFD-induced steatosis and impaired metabolic conversion of the CES1/CES2 substrates, oseltamivir and irinotecan. This deficiency resulted in a corresponding increase in their drug exposure (AUC) by 154.5% and 26.2%, respectively. Mechanistically, LXRα directly bound to liver X receptor response elements (LXREs) in the promoter regions of CES1 (−183/−165 bp) and CES2 (−1870/−1852 bp) to drive transcription in HepG2 cells. Furthermore, ORI (2.5, 5, 10 μM) dose-dependently restored CES1/CES2 expression and activity, reducing lipid accumulation. Silencing of CES1 or CES2 abolished ORI’s lipid-lowering effect, confirming their essential roles. These findings establish the LXRα-CES1/CES2 pathway as a pivotal node integrating hepatic lipid homeostasis and drug metabolism, positioning ORI as a promising therapeutic agent for MASLD.

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Fig. 1: Inhibition of hepatic CES1 and CES2 expression due to LXRα deficiency.
Fig. 2: LXRα deficiency impairs CES1 and CES2 metabolic capacity.
Fig. 3: Activation of LXRα restores the decreased CES1 and CES2 expression caused by HFD-induced obesity.
Fig. 4: LXRα regulates the transcription of CES1 and CES2.
Fig. 5: ORI alleviates TG accumulation and hepatic steatosis through CES1- and CES2-dependent mechanisms.
Fig. 6: ORI induces the expression of CES1 and CES2 in an LXRα-dependent manner.

Data availability

The data supporting the findings of this study are available in the “Methods” section of the article and/or the Supplementary Materials. RNA-seq data were obtained from the GEO database with an accession number of GSE204986. Additional supporting data are available from the corresponding authors upon reasonable request.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 82274002, No. 82473993, No. 82304604), the Key Research and Development Program of Guangdong Province (2024A1515012477, 2023A1515110767), and the Science and Technology Innovation Project of Guangdong Medical Products Administration (2024ZDZ08, China).

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Author notes

  1. These authors contributed equally: Huan-guo Jiang, Zhi-kun Zhan, Ling-min Tian

Authors and Affiliations

  1. Guangdong Provincial Key Laboratory of New Drug Screening, Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China

    Huan-guo Jiang, Ling-min Tian, Mei-qun Cai, Xin Chen, Chuan-liang Wei & Lan Tang

  2. Department of Pharmacy, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China

    Zhi-kun Zhan

  3. Shenzhen Key Laboratory of Chinese Medicine Active Substance Screening and Translational Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China

    Yu-lian Chen

  4. Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China

    Guang-bo Ge

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Contributions

LT, HGJ, and ZKZ designed the research and wrote the paper. HGJ, ZKZ, LMT, YLC, and MQC performed the experiments and contributed to the acquisition and analysis of data. GBG kindly provided the fluorescent probe for CES activity measurement. MQC, XC, and CLW contributed to the data interpretation.

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Correspondence to Lan Tang.

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Jiang, Hg., Zhan, Zk., Tian, Lm. et al. Oridonin exerts dual therapeutic effects in MASLD mice by integrating lipid homeostasis and drug bioactivation via the LXRα–CES1/CES2 pathway. Acta Pharmacol Sin (2026). https://doi.org/10.1038/s41401-025-01737-x

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