Dual-function natural products:Farnesoid X receptor agonist/in-flammation inhibitor for metabolic dysfunction-associated steatotic liver disease therapy
10.1016/S1875-5364(24)60706-5
- Author:
Kang WANG
1
;
Pengfei ZHANG
;
Huiyong SUN
;
Shuang CUI
;
Lanjia AO
;
Ming CUI
;
Xiaowei XU
;
Lin WANG
;
Yuanyuan XU
;
Guangji WANG
;
Hong WANG
;
Haiping HAO
Author Information
1. State Key Laboratory of Natural Medicines,Key Laboratory of Drug Metabolism & Pharmacokinetics,China Pharmaceutical University,Nanjing 210009,China
- Keywords:
FXR agonist;
Inflammation;
Dual modulator;
Natural products;
MASLD
- From:
Chinese Journal of Natural Medicines (English Ed.)
2024;22(11):965-976
- CountryChina
- Language:Chinese
-
Abstract:
Metabolic dysfunction-associated steatotic liver disease(MASLD)is the most prevalent chronic liver disease globally,with only one Food and Drug Administration(FDA)-approved drug for its treatment.Given MASLD's complex pathophysiology,ther-apies that simultaneously target multiple pathways are highly desirable.One promising approach is dual-modulation of the famesoid X receptor(FXR),which regulates lipid and bile acid metabolism.However,FXR agonists alone are insufficient due to their limited anti-inflammatory effects.This study aimed to dto identify natural products capable of both FXR activation and inflammation inhibition to provide a comprehensive therapeutic approach for MASLD.Potential FXR ligands from the Natural Product Library were predicted via virtual screening using the Protein Preparation Wizard module in Schrodinger(2018)for molecular docking.Direct binding and regulation of candidate compounds on FXR were analyzed using surface plasmon resonance(SPR)binding assay,reporter gene ana-lysis,and reverse transcription-polymerase chain reaction(RT-PCR).The anti-inflammatory properties of these compounds were eval-uated in AML12 cells treated with tumor necrosis factor-alpha(TNF-α).Dual-function compounds with FXR agonism and inflamma-tion inhibition were further identified in cells transfected with Fxr siRNA and treated with TNF-α.The effects of these dual-function compounds on lipid accumulation and inflammation were evaluated in cells treated with palmitic acid.Results revealed that 17 natural products were predicted via computational molecular docking as potential FXR agonists,with 15 exhibiting a strong affinity for FXR recombinant protein.Nine isoflavone compounds significantly enhanced FXR reporter luciferase activity and the mRNA expressions of Shp and Ostb.Structure-activity relationship analysis indicated that introducing isopropyl or methoxy groups at the C7 position or a methoxy group at the C6 position could enhance the agonistic efficacy of isoflavones.Three compounds(2,6,and 8)were identified as dual-function natural products functioning as FXR agonists and inflammatory inhibitors,while one compound(12)acted as an FXR agonist to inhibit inflammation.These natural products protected hepatocytes against palmitic acid-induced lipid accumulation and in-flammation.In conclusion,compounds 2,6,and 8(genistein,biochanin A,and 7-methoxyisoflavone,respectively)were identified as dual-function bioactive products that transactivate FXR and inhibit inflammation,serving as potential candidates or lead compounds for MASLD therapy.
