Dimeric guaianolide sesquiterpenoids from the flowers of Chrysanthemum indicum ameliorate hepatic steatosis through mitigating SIRT1-mediated lipid accumulation and ferroptosis

Yu Liu; Fei Zhou; Haoyu Zhao; Jianguo Song; Min Song; Jianzhong Zhu; Ying Wang; Maggie Pui Man Hoi; Ligen Lin; Qingwen Zhang

doi:10.1016/j.jare.2024.12.047

Dimeric guaianolide sesquiterpenoids from the flowers of Chrysanthemum indicum ameliorate hepatic steatosis through mitigating SIRT1-mediated lipid accumulation and ferroptosis

J Adv Res. 2025 Jan 7:S2090-1232(24)00625-8. doi: 10.1016/j.jare.2024.12.047. Online ahead of print.

Authors

Yu Liu¹, Fei Zhou², Haoyu Zhao², Jianguo Song³, Min Song⁴, Jianzhong Zhu⁵, Ying Wang³, Maggie Pui Man Hoi⁶, Ligen Lin⁷, Qingwen Zhang⁸

Affiliations

¹ State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macao 999078, China; Guangdong-Hong Kong-Macau Join Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, University of Macau, Avenida da Universidade, Taipa, Macao 999078, China.
² State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macao 999078, China.
³ State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou 510632, China; Guangdong-Hong Kong-Macau Join Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, China.
⁴ Guangdong Provincial Engineering Research Center for Modernization of TCM, Jinan University, Guangzhou 510632, China.
⁵ Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
⁶ State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macao 999078, China; Department of Pharmaceutical Sciences and Technology, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macao 999078, China.
⁷ State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macao 999078, China; Department of Pharmaceutical Sciences and Technology, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macao 999078, China. Electronic address: ligenl@um.edu.mo.
⁸ State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macao 999078, China; Guangdong-Hong Kong-Macau Join Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, University of Macau, Avenida da Universidade, Taipa, Macao 999078, China; Department of Pharmaceutical Sciences and Technology, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macao 999078, China. Electronic address: qwzhang@um.edu.mo.

PMID: 39788286
DOI: 10.1016/j.jare.2024.12.047

Abstract

Introduction: Non-alcoholic fatty liver disease (NAFLD) acts as the primary contributor to non-alcoholic steatohepatitis, fibrosis, cirrhosis, and potentially hepatocellular carcinoma. The flowers of Chrysanthemum indicum, a traditional edible medicinal herb, have been widely used in China for more than 2000 years. However, the function of C. indicum in managing NAFLD has seldom been investigated.

Objectives: To reveal the novel active components and underlying mechanisms of C. indicum in treating NAFLD.

Methods: An MS/MS-based molecular networking-guided strategy was used for the chemical investigation. The structure identification of the new compounds involved high resolution electrospray ionization mass spectrometry (HRESIMS), 1D and 2D nuclear magnetic resonance (NMR) spectra, electronic circular dichroism (ECD), and X-ray crystallographic analysis. The biological evaluation was performed using Nile Red staining, flow cytometry, commercial kits, western blotting, co-immunoprecipitation, isothermal titration calorimetry, cellular thermal shift assay, drug affinity responsive target stability assay, molecular docking, and confocal immunofluorescence.

Results: A total of 27 new dimeric sesquiterpenoids, chryindicolides A-Z (1-26) and chrysanthemolide C (27), together with seven known compounds, were isolated from the flowers of C. indicum under the guide of MS/MS-based molecular networking. Among them, compounds 1-7 were rare chlorine-containing guaianolide dimers. Chryindicolide O (15) directly bound and activated the deacetylase Sirtuin 1 (SIRT1) to reduce de novo lipogenesis, enhance fatty acid β-oxidation, and inhibit ferroptosis in palmitic acid and oleic acid (P/O)-induced AML12 hepatocytes. In addition, chryindicolide O significantly ameliorated liver steatosis in high-fat diet-fed zebrafish.

Conclusion: Novel guaianolide dimers from C. indicum alleviated hepatic steatosis through mitigating SIRT1-mediated lipid accumulation and ferroptosis, suggesting that they could be further developed as candidates against NAFLD.

Keywords: Chrysanthemum indicum; Dimeric guaianolide sesquiterpenoids; Ferroptosis; Molecular networking; Non-alcoholic fatty liver disease; SIRT1.