Identification of chikusetsusaponin IVa as a novel lysine-specific demethylase 1 inhibitor that ameliorates high fat diet-induced MASLD in mice  

作　　者：Yu-wen Liu Ru-yue Luo An-qi Liu Jia-wei Wang Na-ping Hu Wang-ting Li Jian-kang Li Jing-wen Wang Jia-lin Duan 

机构地区：[1]Xi’an Key Laboratory of Stem Cell and Regenerative Medicine,Institute of Medical Research,Northwestern Polytechnical University,Xi’an,710072,China [2]Department of Pharmacy,General Hospital of Xinjiang Production and Construction Corps,Urumqi City,830092,Xinjiang Uygur Autonomous Region,China [3]Department of Pharmacy,Xijing Hospital,FourthMilitaryMedicalUniversity,Xi'an710032,China

出　　处：《Acta Pharmacologica Sinica》2025年第3期632-652,共21页中国药理学报(英文版)

基　　金：supported by the National Natural Science Foundation of China(81903832);Key Research and Development Plan of Shaanxi Province(2022SF-182);Fundamental Research Funds for the Central Universities(D5000210799);Shaanxi Provincial Traditional Chinese Medicine Administration“Double Chain Integration”Middle Youth Research and Innovation Team Project(2022-SLRH-LJ-007);Shanghai Science and Technology Innovation Action Plan(22S21902600).

摘　　要：Diet-induced metabolic dysfunction steatotic liver disease(MASLD)is also called as non-alcoholic fatty liver disease(NAFLD)with limited effective strategies available.We previously have shown that chikusetsusaponin IVa(CHS),a dietary saponin from herbs in South American known for their metabolic benefits,mitigates diet-induced diabetes.In this study we investigated the beneficial effects of CHS on MASLD and the underlying mechanisms.MAFLD mouse model was established by the high-fat diet(HFD)for 6 weeks and then were treated with CHS(50 mg·kg^(-1)·d^(-1),i.g.)for another 8 weeks.By conducting transcriptomic analysis in palmitic acid-treated HepG2 cells and primary hepatocytes as well as lipidomic analysis in liver tissues,we demonstrated that HFD activated the intestinal farnesoid X receptor(FXR)pathway,leading to the release of FGF15/19,which in turn promoted hepatic FXR-SHP binding with cAMP-responsive element-binding protein H(CREBH),thereby inhibiting CREBH-mediated fatty acid oxidation(FAO)and ketogenesis.Intriguingly,we found that CHS improved lipid metabolism in HFD mice by suppressing the enterohepatic crosstalk of FXR-SHP to enhance CREBH transactivation.Among these,lysine-specific demethylase 1(LSD1)-mediated histone demethylation played a crucial role in lipid metabolic reprogramming.Moreover,we identified LSD1 as a critical cellular target of CHS,directly binding to Lys661 and Tyr761 of LSD1 to inhibit its histone demethylation activity.Our results suggest that targeting intestinal LSD1 with CHS could be a promising strategy for MAFLD treatment,offering new insights into the bioavailability and efficacy of natural products.

关 键 词：MASLD chikusetsusaponin Iva LSD1 fatty acid oxidation FXR/SHP CREBH 

分 类 号：R285[医药卫生—中药学]