High-fat diet (HFD)–induced obesity disrupts hepatic lipid metabolism and alters gut microbiota composition, contributing to steatosis, inflammation, and metabolic dysfunction. Puerarin, a natural isoflavone, possesses lipid-lowering and metabolic regulatory properties but is limited by low solubility and bioavailability. Liposomal encapsulation enhances therapeutic delivery and stability. This study explores whether puerarin encapsulated liposomes (PUE-LIPs) attenuate HFD-induced lipid dysregulation by modulating the SREBP-1/FAS/CD36 signaling axis and remodeling gut microbiota. To investigate the effects of PUE-LIPs on hepatic lipid metabolism, adiposity, and gut microbial composition in HFD-fed rodents, and to elucidate their mechanistic actions on the SREBP-1/FAS/CD36 pathway.

PUE-LIPs were formulated via thin-film hydration and characterized for particle size, polydispersity, zeta potential, encapsulation efficiency, and in vitro release behavior. Rodents were fed an HFD for 12–16 weeks and subsequently treated with free puerarin or PUE-LIPs. Metabolic parameters including body weight, serum lipids, liver enzymes, and glucose tolerance were assessed. Hepatic histology (H&E, Oil Red O), TEM, and lipid quantification were performed. Expression of SREBP-1, fatty acid synthase (FAS), and CD36 was analyzed using qPCR, Western blotting, and immunohistochemistry. Fecal 16S rRNA sequencing was conducted to evaluate gut microbial diversity, abundance, and functional shifts.

PUE-LIPs displayed uniform nano-scale size, high encapsulation efficiency, and controlled release. HFD-fed rodents exhibited marked hepatic steatosis, elevated SREBP-1 and FAS expression, and increased CD36-mediated fatty acid uptake, accompanied by gut dysbiosis characterized by reduced microbial diversity and increased obesogenic taxa. PUE-LIP treatment significantly reduced body weight gain, serum triglycerides, and hepatic lipid accumulation compared with free puerarin. Mechanistically, PUE-LIPs downregulated SREBP-1/FAS-driven lipogenesis, suppressed CD36-mediated fatty acid transport, and restored gut microbial balance by enriching short-chain fatty acid–producing genera and reducing pro-inflammatory Bacteroides and Firmicutes overgrowth.

Puerarin-encapsulated liposomes effectively alleviate HFD-induced obesity and hepatic steatosis by inhibiting lipogenesis, limiting fatty acid uptake via the SREBP-1/FAS/CD36 pathway, and reshaping gut microbiota toward a metabolically favorable profile. Liposomal delivery significantly enhances puerarin’s bioactivity, supporting its potential as a novel nanotherapeutic strategy for metabolic disorders.