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

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/6J 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.