Nanoparticle-Based Oral Delivery of Berberine Attenuates High-Fat Diet-Induced Hepatic Steatosis in Mice: Insights from Integrated Hepatic Metabolomic and Transcriptomic Analyses

NAFLD-related hepatic steatosis is a growing global health concern. We developed food-grade gliadin hydrolysate–berberine–chitosan nanoparticles (BBR-NPs) and evaluated their bioactivity in oleic acid-challenged HepG2 cells and high-fat diet (HFD)-fed mice. In vitro, BBR-NPs reduced triglycerides, total cholesterol, and LDL-C, increased HDL-C, and alleviated oxidative stress by decreasing ROS and malondialdehyde while enhancing superoxide dismutase activity. In vivo, oral BBR-NPs attenuated hepatic lipid deposition and improved serum/hepatic lipid indices, ALT/AST, oxidative stress markers, insulin resistance, and inflammatory cytokines, with generally more pronounced effects than free berberine at the same nominal dose in this model. Integrated hepatic metabolomics and transcriptomics suggested coordinated regulation of lipid homeostasis, including fatty acid oxidation, de novo lipogenesis, and cholesterol/bile acid metabolism. Collectively, BBR-NPs represent a scalable oral delivery approach that may enhance berberine’s metabolic benefits in diet-induced steatosis; however, pharmacokinetic and tissue exposure studies are needed to confirm formulation-specific advantages.