Qingqing Zhang, Chongzheng Pang, Lehua Chen, Ruikai Yan, Xue Yu, Baohua Chen, Baoku Li, Chengyan Zhou
Alcoholic liver disease (ALD) is a major global health burden. Cuproptosis, a form of regulated cell death, plays a critical role in multiple liver diseases, yet its role and mechanisms in ALD remain largely unknown. This study explored the preventive and therapeutic roles of mangiferin monosodium salt (MG-Na) against ALD and the associated gut-liver axis mechanisms. ALD was induced in rats via chronic alcohol administration, with or without MG-Na treatment. Liver function and intestinal barrier integrity were assessed. Next, gut microbial composition and ALD-associated metabolic alterations were assessed by 16S rRNA gene sequencing and fecal metabolomics. Proteins and factors involved in alcohol metabolism, the TCA cycle, cuproptosis, and inflammation were subsequently analyzed using Western blotting, qRT-PCR, ICP-MS, immunohistochemistry, and ELISA. The results showed that MG-Na improved liver function and intestinal barrier integrity, and ameliorated alcohol metabolic dysfunction, TCA cycle impairment, cuproptosis, and alcoholic hepatitis. Also, MG-Na markedly affected gut microbiota diversity and community richness. Meanwhile, MG-Na reduced the production of fecal metabolites in ALD rats, such as (R)-lipoic acid and pyruvic acid. Notably, MG-Na downregulated proteins involved in alcohol metabolism (ADH1, CYP2E1), cuproptosis (FDX1, DLAT), cGAS-STING and TLR4/NF-κB/NLRP3 pathways, while increasing TCA cycle-related enzyme activity and metabolite levels in the liver, though some changes were not statistically significant. And, MG-Na administration can also significantly decrease the levels of pro-inflammatory cytokines (IFN-β, TNF-α, IL-1β and IL-6) and increase the anti-inflammatory cytokine (IL-10) level. Together, these results suggested that MG-Na can attenuate metabolic and alcoholic hepatitis by modulating gut microbiota, inhibiting cuproptosis, and suppressing inflammatory responses.