Protective effects of a herbal combination (Dimocarpus longan and Orthosiphon stamineus) on metabolic-associated fatty liver disease via the ERα-PI3K-AKT pathway.

Metabolic dysfunction-associated fatty liver disease (MAFLD), which affects over 35% of the global adult population, currently lacks therapies that are safe, well tolerated, and suitable for long-term use. To enable safe and long-term intervention, we aimed to identify the optimal formulation and therapeutic value from several herbal plants while ensuring palatability for better acceptance. We evaluated the synergistic effects of Siraitia grosvenorii (monk fruit), Dimocarpus longan (longan), and Orthosiphon stamineus (misai kucing) on MAFLD. Utilizing in vivo/in vitro models, we demonstrated that the longan-misai kucing combination exhibits synergistic anti-inflammatory and hepatic lipid-clearing efficacy, surpassing that of individual monotherapies. Quinic acid and tormentic acid were further identified as key bioactive compounds of longan and misai kucing, targeting ERα and PI3K/AKT pathways via direct binding to PIK3CA, PIK3CB, and ESR1. These compounds synergistically reduced hepatic triglycerides (-59.3%) and cholesterol (-35.2%) levels, body fat mass (23.3%), and adipose tissue weight (inguinal: 39.6%; epididymal: 26.2%). This study demonstrated that the combination of longan and misai kucing activates the ERα-PI3K-AKT pathway to alleviate hepatic steatosis, which provides a pharmacodynamic basis for developing multi-herbal therapies against metabolic disorders.