Graphene Oxide Nanoparticles Mediated Protective Effect Against the Ethanol Induced Gut-Liver Axis by Targeting miRNA-203a and miRNA-122

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Abstract
Alcohol-associated liver disease (ALD) is driven by complex interactions among hepatic lipid accumulation, oxidative stress, inflammation, cell death, and disruption of the gut–liver axis. Therapeutic strategies capable of targeting multiple interconnected pathogenic pathways remain limited. In this study, we investigated the protective potential of graphene oxide nanoparticles (GNPs) in a chronic ethanol-fed rat model of ALD. Male Wistar rats were subjected to ethanol feeding and intermittently treated with GNPs (10 mg/kg) by oral gavage. Hepatic injury was assessed by biochemical parameters, histology, lipid accumulation, gene and miRNA expression, protein analysis, and gut microbiome profiling. Ethanol feeding induced hepatic steatosis, oxidative stress, apoptotic and necroptotic signaling, intestinal barrier disruption, gut dysbiosis, and activation of hepatic inflammatory pathways. GNP treatment markedly attenuated ethanol-induced lipid accumulation, normalized liver morphology, and reduced biochemical markers of liver injury. These effects were accompanied by restoration of antioxidant defenses, including Nrf2 and HO-1, and suppression of CYP2E1 expression and cell death–associated markers. In parallel, GNPs preserved intestinal architecture, maintained tight junction gene expression, and suppressed intestinal inflammatory responses. Gut microbiome analysis revealed partial restoration of ethanol-induced dysbiosis, including recovery of beneficial postbiotic-associated bacterial taxa. Improved intestinal homeostasis was associated with attenuation of hepatic TLR4-associated inflammatory signalling and modulation of macrophage-associated markers. Furthermore, GNP treatment partially normalized ethanol-induced dysregulation of miRNAs implicated in lipid metabolism, inflammation, and oxidative stress. Collectively, these findings demonstrate that GNPs exert a coordinated protective effect against ethanol-induced liver injury by modulating multiple pathological processes along the gut–liver axis. This multi-targeted activity highlights the therapeutic potential of graphene oxide nanoparticles as an intervention strategy for early-stage alcohol-associated liver disease.

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