2. Academic Validation
  3. Moronic acid alleviates non-alcoholic fatty liver disease and fibrosis through PPARs-mediated lipidomic reprogramming

Moronic acid alleviates non-alcoholic fatty liver disease and fibrosis through PPARs-mediated lipidomic reprogramming

  • Phytomedicine. 2025 Dec:149:157519. doi: 10.1016/j.phymed.2025.157519.
Jinlu Han 1,  Jiong Chen 1,  Hong Hu 1,  Yun Song 1,  Mengyan Chen 1,  De Zhao 1,  Wen Shan 2,  Qinghui Zhang 3,  Ling Xu 4
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Tongren Hospital, Shanghai Jiaotong University School of Medicine, 1111 Xianxia Road, Shanghai, 200336, China.
  • 2 Department of Thoracic Surgery and Cardiac Surgery, No. 2 People's Hospital of Fuyang City, Fuyang, No. 1088, Yinghe West Road, 236015, China.
  • 3 Department of Clinical laboratory, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 Xianxia Road, Shanghai, 200336, China. Electronic address: [email protected].
  • 4 Department of Gastroenterology, Tongren Hospital, Shanghai Jiaotong University School of Medicine, 1111 Xianxia Road, Shanghai, 200336, China. Electronic address: [email protected].
PMID: 41242309 DOI: 10.1016/j.phymed.2025.157519
Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) and its fibrotic progression represent major global health concerns with limited pharmacological interventions. Moronic acid (MA), a natural pentacyclic triterpenoid, has demonstrated anti-inflammatory and metabolic activity, but its role in NAFLD and fibrosis remains unclear.

Purpose: This study aimed to elucidate the therapeutic potential and mechanism of MA in ameliorating NAFLD and liver fibrosis.

Methods: The therapeutic effects of MA were evaluated in C57BL/6 J mouse models of NAFLD and fibrosis. An integrated multi-omics approach, combining network pharmacology, proteomics, and lipidomics, was used to investigate the underlying mechanism. Direct binding to the identified target, peroxisome proliferator-activated receptors (PPARs), and cellular engagement were confirmed by microscale thermophoresis (MST) and Cellular Thermal Shift Assay (CETSA). The dependency on this pathway was genetically validated using siRNA-mediated gene silencing and further confirmed in a 3D human liver Organoid model.

Results: MA alleviated hepatic steatosis, fibrosis, and metabolic dysregulation in both models. MA activated PPARα/β/γ, as evidenced by molecular docking, dynamics simulations, and increased hepatic expression. In hepatocytes and hepatic stellate cells, MA reduced lipid accumulation and fibrogenesis, effects reversed by PPAR inhibition. Lipidomic profiling showed that MA upregulated glycerophospholipids and sphingolipids and downregulated glycerolipids, consistent with PPAR-driven lipid remodeling.

Conclusion: MA exerts therapeutic effects against NAFLD and fibrosis through PPAR activation and lipidomic reprogramming. These findings support the potential of MA as a novel phytotherapeutic agent for metabolic liver disease.

Keywords

3D liver model; Lipidomics; Liver fibrosis; Moronic acid; Non-alcoholic fatty liver disease; Peroxisome proliferators-activated receptors.

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