Phyllanthus niruri niosomes ameliorate obesity-induced hepatic steatosis in rats via modulating MALAT1/miR-206/GLP-1R signaling and hepatic lipid metabolism.

Metabolic dysfunction associated fatty liver disease (MAFLD) is a rapidly growing global health burden characterized by hepatic lipid accumulation, insulin resistance, oxidative stress, and inflammation. Phyllanthus niruri (PHYLN) is rich in polyphenols and lignans with known antioxidant and anti-inflammatory properties; however, its therapeutic efficacy is limited by poor bioavailability. This study investigated the protective potential of PHYLN extract loaded into niosomal nanocarriers (PHYLN-NIO) against obesity-induced hepatic steatosis and explored its mechanistic similarity to glucagon-like peptide-1 receptor agonists (GLP-1RAs). Rats were divided into seven groups: control, PHYLN-NIO, HFD, HFD + Semaglutide, HFD + Semaglutide + exendin 9–39, HFD + PHYLN-NIO, and HFD + PHYLN-NIO + exendin 9–39. PHYLN-NIO markedly reduced body weight and body mass index, hepatic steatosis, and inflammation, while enhancing antioxidant status, insulin sensitivity, and lipid profiles. Mechanistically, PHYLN-NIO modulated the lncRNA-MALAT1/miR-206 axis, restored GLP-1/GLP-1R signaling, and downregulated key hepatic lipogenic regulators (LXR-α, SREBP-1c, FASN, ACC-1), while upregulating genes involved in fatty acid oxidation and metabolic homeostasis (FXR, PPAR-α, FOXA2). Notably, co-administration of exendin 9–39 reversed these effects, confirming a GLP-1R-dependent mechanism. These findings suggest that PHYLN-NIO effectively targets MALAT1/miR-206/GLP-1R signaling pathways, demonstrating its potential as a promising nanotherapeutic candidate for MAFLD management.