Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a growing global health challenge, necessitating the discovery of safe and effective therapeutic agents from natural dietary sources. Zanthoxylum bungeanum Maxim. (huajiao), a widely consumed pharma-food, contains abundant alkaloids with reported lipid-regulating, antioxidant, and anti-inflammatory activities, but its underlying mechanisms against MASLD remain unclear. This study aimed to evaluate the hepatoprotective effects of alkaloids from Z. bungeanum (ZBA) and elucidate its molecular targets using an integrated approach combining network pharmacology, transcriptomics, and experimental validation. To this end, FFAs-stimulated HepG2 cells and HFD-fed mice were employed to assess the effects of ZBA. The results showed that ZBA significantly alleviated hepatic lipid accumulation, improved insulin sensitivity, and reduced systemic inflammation. Mechanistically, omics analysis and molecular docking predicted the endocannabinoid system as a key target, and the cellular thermal shift assay confirmed that ZBA directly binds to both CB1 and CB2 receptors. Furthermore, pharmacological interventions using specific agonists and antagonists revealed that ZBA exerts a dual modulatory effect on the endocannabinoid system by suppressing CB1 overexpression and enhancing CB2 activity. This modulation subsequently activates the Akt/GSK3β/Nrf2 signaling cascade to restore lipid metabolism homeostasis and mitigate lipotoxicity in a dose-responsive regulatory trend. In conclusion, the present findings highlight that ZBA ameliorates MASLD by rebalancing the expression of CB1 and CB2 receptors, thereby modulating Akt/GSK3β/Nrf2 axis, thus providing a scientific basis for the development of ZBA as a functional food ingredient for metabolic health.

Increasing the osteogenic differentiation ability and decreasing the adipogenic differentiation ability of bone marrow mesenchymal stem cells (BMSCs) is a potential strategy for the treatment of osteoporosis (OP). Naturally derived oligosaccharides have shown significant anti-osteoporotic effects. Nystose (NST), an oligosaccharide, was isolated from the roots of Morinda officinalis How. (MO). The aim of the present study was to investigate the effects of NST on bone loss in ovariectomized mice, and explore the underlying mechanism of NST in promoting differentiation of BMSCs to osteoblasts. Administration of NST (40, 80 and 160 mg/kg) and the positive control of estradiol valerate (0.2 mg/kg) for 8 weeks significantly prevented bone loss induced by ovariectomy (OVX), increased the bone mass density (BMD), improved the bone microarchitecture and reduced urine calcium and deoxypyridinoline (DPD) in ovariectomized mice, while inhibited the increase of body weight without significantly affecting the uterus weight. Furthermore, we found that NST increased osteogenic differentiation, inhibited adipogenic differentiation of BMSCs in vitro, and upregulated the expression of the key proteins of BMP and Wnt/β-catenin pathways. In addition, Noggin and Dickkopf-related protein-1 (DKK-1) reversed the effect of NST on osteogenic differentiation and expression of the key proteins in BMP and Wnt/β-catenin pathway. The luciferase activities and the molecular docking analysis further supported the mechanism of NST. In conclusion, these results indicating that NST can be clinically used as a potential alternative medicine for the prevention and treatment of postmenopausal osteoporosis.