Pueraria montana var. lobata Root Extract Alleviates Metabolic Dysfunction‐Associated Steatotic Liver Disease by Increasing Mitochondrial β‐Oxidation and Mitochondrial‐Peroxisome Contact

Pueraria montana var. lobata (Willd.) is a well-known herbal medicine, also referred to as "kudzu." It is used in traditional Chinese medicine to treat various medical conditions, including diabetes, cardiovascular diseases, diarrhea, and hypertension. Additionally, Pueraria montana var. lobata is considered a functional food widely recognized to enhance the immune system and treat hyperlipidemia. We aim to evaluate the effects of Pueraria montana var. lobata extract (PLE) on the development of inflammation and the progression to metabolic dysfunction-associated steatotic liver disease (MASLD) by investigating the effects and underlying mechanisms both in vivo and in vitro under metabolic stress. To address whether PLE can reverse established MASLD/fibrosis, we performed a robust hepatosteatosis study in mice fed with a Western diet (WD) and PLE. AML12 and HepG2 cells were exposed to OA and/or PA at different concentrations and combinations. Intracellular lipids and cell viability were detected with Oil Red O staining and CCK8 assay, respectively. Confocal microscopy was employed to analyze mitochondrial functions and their relative positions to peroxisomes. PLE treatment significantly reduced lipid accumulation, inflammatory response, liver injury, and fibrosis in mice fed a high-fat diet. RNA-sequencing indicated that the key mechanism underlying the anti-MASLD effects of PLE was higher peroxisome activity and the subsequent increase in β-oxidation flux. PLE concurrently decreased cholesterol-raising saturated fatty acids and increased polyunsaturated fatty acids (PUFAs) and monounsaturated fatty acids (MUFAs) in AML12 mouse liver cells treated with OA. Confocal images revealed the intracellular transport route between mitochondria and peroxisomes after PLE treatment. There are currently no FDA-approved therapies for MASLD. Our study demonstrates that PLE prevents metabolic stress-induced MASLD progression through direct activation of CPT1A signaling, suggesting that PLE may be considered a therapeutic candidate for the treatment of MASLD.