Silymarin-loaded phytosomal nanoparticles mitigate dyslipidemia, oxidative damage, and hepatic injury in high-fat diet-induced metabolic dysfunction-associated steatotic liver disease in rats

High-fat diets (HFDs) play a central role in the onset and progression of metabolic syndrome. This study investigated the protective effects of silymarin (SM)-loaded phytosomal nanoparticles (SM-PNPs) against high-fat diet (HFD)-induced hepatic dysfunction and metabolic disorders, with emphasis on antioxidant and anti-inflammatory mechanisms. Sixty rats were randomly divided into six groups: control, SM-treated (200 mg/kg body weight), SM-PNPs-treated (200 mg/kg body weight), HFD-treated, and two combination groups receiving HFD along with either SM or SM-PNPs (200 mg/kg body weight) for 5 weeks during the final phase of a 20-week HFD feeding period. SM-PNPs therapy demonstrated stronger hepatoprotective activity than unencapsulated SM. It significantly improved metabolic abnormalities, including insulin resistance, dyslipidemia, and hepatopathy in HFD-fed rats. Moreover, SM-PNPs ameliorated HFD-induced alterations in fasting glucose and insulin levels and improved HOMA-IR indices, thereby restoring glucose homeostasis. Treatment also markedly reduced oxidative stress while enhancing the antioxidant defense system. RT-PCR analysis revealed significant downregulation of key inflammatory genes, including interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), nuclear factor kappa B (NF-κB), and inducible nitric oxide synthase (iNOS), along with a significant reduction in systemic inflammation, as indicated by decreased high-sensitivity C-reactive protein (hsCRP) levels, as well as apoptosis caspases activities. The in-silico analysis revealed significant interactions of SM with crucial proteins involved in regulating antioxidant defense and inflammatory pathways. Histopathological and ultrastructural examinations further supported these biochemical findings, showing that SM-PNPs attenuated hepatic steatosis, collagen deposition, and fibrosis. SM-PNPs exert a significant protective effect against HFD-induced hepatic damage and metabolic disturbances and represent a promising therapeutic strategy for metabolic dysfunction-associated steatotic liver disease (MASLD), potentially due to improved solubility, bioavailability, and sustained release in the nanoparticle formulation. The graphical abstract illustrates the protective effects of silymarin-loaded phytosomal nanoparticles (SM-PNPs) against liver and metabolic disorders induced by a high-fat diet (HFD). SM-PNPs significantly mitigate oxidative stress by enhancing the activities of glutathione peroxidase, superoxide dismutase, and catalase. They decrease the levels of TNF-α, IL-1β, IL-6, and CRP to inhibit inflammation and lower the levels of caspases-3, -8, and − 9 to prevent apoptosis. Additionally, SM-PNPs exhibit antifibrotic effects by decreasing TGF-β expression. These mechanisms collaborate to prevent hepatic steatosis, fibrosis, and metabolic dysfunction-associated steatotic liver disease (MASLD).