PubMedPhytomedicine : international journal of phytotherapy and phytopharmacology2026-10-15
Mechanistic insights into the therapeutic effects of Mongolian medicine Eligengurigumu-7 against non-alcoholic fatty liver disease via the PPAR signalling pathway.
Huang Congying C, Wu Huijun H, Zhang Shen S, Feng Wanze W et al.
Non-alcoholic fatty liver disease (NAFLD)， is characterised by a complex, multi-stage pathogenesis and progression and imposes a substantial economic burden on global public health. Thus, an urgent need exists to improve the understanding of NAFLD-related hepatic disease progression and identify effective therapeutic strategies. Eligengurigumu-7 (GRGM-7) is a common treatment prescription for liver diseases in Mongolian medicine. However, its pharmacodynamics and mechanism of action remain largely unclear.
To evaluate the hepatoprotective efficacy of GRGM-7 against NAFLD, identify its bioactive constituents absorbed into the bloodstream, and elucidate its key molecular targets and underlying regulatory pathways.
The key differentially expressed genes (DEGs) and pathways during the progression of NAFLD-related hepatic diseases were identified through bioinformatics analysis and immunofluorescence validation of clinical samples. NAFLD mouse models induced with either a high-fat diet (HFD) or a methionine- and choline-deficient diet (MCD) were established. The therapeutic effects of GRGM-7 against NAFLD were evaluated in these models by comparing the physiological, biochemical, and pathological indicators of the control groups, model groups, and each dose treatment group. Through RNA-sequencing and non-targeted metabolomics analysis and the combined analysis of multi-source datasets, the key pharmacodynamic targets, regulatory function directions, and regulatory pathways of GRGM-7 involved in improving NAFLD were identified and verified through reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting (WB) experiments. The chemical components of GRGM-7 were identified using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS), and the compounds absorbed into the bloodstream (CABs) were identified and analysed based on the principles of serum pharmacochemistry. CABs were quantitatively analysed in the original herbal formulation through high-performance liquid chromatography (HPLC), and molecular docking was used to analyse the interaction between the CABs and active targets. The hepatoprotective effects of CABs and GRGM-7, as well as their effects on the targets were confirmed in an in vitro NAFLD model of oleic acid-induced AML-12 cells. Additionally, PPARγ and ACLY were subjected to siRNA-mediated silencing, and fenofibrate was used as a pharmacological agonist of PPARα to further functionally validate the involvement of the PPAR signaling pathway and ACLY in the effects of GRGM-7.
Peroxisome proliferator-activated receptor (PPAR) signalling was a crucial pathway involved in NAFLD-related hepatic disease progression. GRGM-7 administration ameliorated MCD- and HFD-induced NAFLD in mice and protected the liver by regulating the PPAR signalling pathway, promoting fatty acid metabolism, and maintaining liver lipid homeostasis. ATP citrate lyase (ACLY) served as a key candidate target associated with the progression of NAFLD and therapeutic action of GRGM-7. GRGM-7 contained several chemical components that were absorbed into the bloodstream. Among these CABs, cosmosiin exhibited a high affinity for key DEGs and crucial targets within signalling pathways. Moreover, cosmosiin showed a favourable hepatoprotective effect on the NAFLD cell model induced in vitro. GRGM-7 exhibited the strongest hepatoprotective effect in vitro, accompanied by modulation of the PPAR signalling pathway. Silencing of ACLY or PPARγ alleviated metabolic abnormalities, whereas subsequent GRGM-7 treatment produced further improvements. Fenofibrate treatment similarly ameliorated the OA-induced metabolic abnormalities, whereas combined treatment with fenofibrate and GRGM-7 further enhanced these effects, supporting the involvement of the PPAR signalling pathway and ACLY in the metabolic effects of GRGM-7.
PPAR signalling was the key pathway involved in the progression of NAFLD-related hepatic diseases, and ACLY was one of the key potential targets. GRGM-7 regulated the PPAR signalling pathway by modulating fatty acid metabolism, thereby exerting a hepatoprotective effect. These findings highlight the potential utility of GRGM-7 as a therapeutic agent for NAFLD.