Sesamol-loaded PLGA nanoparticles attenuate HFD-induced MASLD by modulating Nrf2/HO-1, mitochondria cascade, and TLR4/NF-κB signaling pathways in rats.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent metabolic disorder defined by excessive lipid accumulation in hepatocytes. This buildup can trigger a cascade of inflammation, oxidative stress, and apoptosis, leading to progressive hepatic injury. The incidence of MASLD has augmented in parallel with obesity and metabolic syndrome, emphasizing the need for effective therapeutic strategies targeting key pathogenic pathways. This study explored the defensive activity of sesamol (SM) or a sesamol-loaded PLGA nanoparticles (SM-PLGA) against high-fat diet (HFD)-induced hepatic damage in rats over a 20-week period, focusing on anti-inflammatory, antioxidant, and anti-apoptotic mechanisms. Sixty adult male albino rats were randomly assigned to six groups: control, SM, SM-PLGA, HFD, HFD + SM, and HFD + SM-PLGA, with oral administration of SM or SM-PLGA (50 mg/kg) during the final four weeks of the study. HFD administration led to dyslipidemia (P < 0.0001), elevated liver enzymes (P < 0.0001), suppression of hepatic Nrf2, HO-1, and NQO1 expression (P < 0.0001), and reduced activities of GSH, CAT and GSH-Px (P < 0.0001). Furthermore, there was an increase in oxidative stress markers such as MDA, ROS, and 8-OHdG (P < 0.0001) in HFD group. In the HFD group, rats exhibited mitochondrial dysfunction (P < 0.0001) alongside a robust inflammatory response, characterized by elevated TLR4/NF-κB signaling and cytokine production (TNF-α, IL-1β, and IL-6) compared to other groups (P < 0.0001). This environment promoted programmed cell death, as evidenced by a pro-apoptotic shift in the Bax/Bcl-2 ratio and increased caspase-3 activity (P < 0.0001). Notably, SM-PLGA exhibited superior therapeutic efficacy, restoring antioxidant homeostasis and suppressing the TLR4/NF-κB inflammatory axis (P < 0.0001). This formulation further mitigated hepatic injury by inhibiting apoptosis, normalizing mitochondrial function, and preserving both histological and ultrastructural integrity. These findings demonstrate that the SM nano-formulation significantly enhances bioactivity, providing robust hepatoprotection against HFD-induced oxidative stress, inflammatory cascades, and apoptosis. Consequently, SM-PLGA emerges as a potent therapeutic candidate for the mitigation of MASLD and associated metabolic liver disorders.