Lysionotin nanoparticles ameliorate ethanol-elicited liver damage by inhibiting hepatocyte ferroptosis and modulating the gut-liver axis.

Alcohol-related liver disease (ALD) represents a worldwide health concern characterized by an increasing incidence and a shortage of therapeutic measures. Lysionotin, a multifunctional flavonoid with low oral bioavailability, has the potential to counteract ethanol-elicited liver damage, but its potential to counteract ethanol-induced liver injury remains unexplored. In this study, lysionotin nanoparticles (Lys-NPs) were prepared using a microplanetary ball milling technique to enhance oral bioavailability, and their hepatoprotective effects against ALD were evaluated using a well-characterized in vivo mouse model. Lys-NPs had an average particle size of 329.7 ± 6.7 nm and exhibited good stability, increased solubility, and enhanced oral bioavailability compared to raw lysionotin. Assessment of serum aminotransferase activities and histopathological changes revealed that Lys-NPs were more effective than the raw compound in preventing ethanol-induced liver damage. Mechanistically, Lys-NPs suppressed ethanol-induced iron accumulation, oxidative stress, GPX4 downregulation, and ACSL4 upregulation in the liver, suggesting that Lys-NPs may ameliorate ethanol-induced hepatocyte ferroptosis. Furthermore, Lys-NPs normalized serum lipopolysaccharide (LPS) levels and inhibited ethanol-induced NF-κB phosphorylation and NLRP3 inflammasome activation. Collectively, these results demonstrate that Lys-NPs can mitigate ALD possibly by suppressing ethanol-induced ferroptosis and modulating the gut-liver axis.