Gold Nanoparticles (AuNPs) Coadministered with a β-Blocker Prevent Liver Fibrosis Caused by Ethanol and Methamphetamine in Rats by Downregulating the Expression of M2 Macrophages.

Simultaneous abuse of ethanol and methamphetamine (METH) causes severe liver damage through oxidative stress and inflammation. This study evaluated the antifibrotic effects of gold nanoparticles (AuNPs) coadministered with the β-blocker carvedilol (CARV) against liver damage in rats. Male Wistar rats received 30% ethanol (7 g/kg) daily for 28 days, with METH (10 mg/kg) administered on the 22nd and 28th days. Liver damage was assessed using serum hepatic enzymes, glutathione (GSH) levels, malondialdehyde (MDA) formation, myeloperoxidase (MPO) inhibition, and histopathological analysis, including H&E, Picrosirius Red staining, immunofluorescence, and transmission electron microscopy. Cytokine levels were measured in liver tissue samples. In vitro, RAW 264.7 macrophages were induced to polarize into M1 and M2 phenotypes and cocultured with AuNPs + CARV-treated 3T3 cells, analyzed by rtPCR. AuNPs + CARV effectively protected the liver by modulating interactions between hepatic stellate cells (HSCs) and Kupffer cells, promoting an antifibrotic immune response driven by M1 macrophages. This was indicated by downregulation of profibrotic M2 macrophages and upregulation of M1 macrophages, shown by an increased CD86/CD163 ratio and reduced levels of IL-1β, TNF-α, TGFβ, AKT, and PI3K., pointing an attenuated liver inflammation. These results suggest that AuNPs combined with CARV could potentially serve as a therapy for alcohol and METH-induced liver fibrosis by targeting M2 macrophages.