Drug repurposing of glucosamine to ameliorate alcoholic liver disease and delay liver aging through activation of AMPK signaling pathway.

Alcohol consumption is a major etiological factor for alcoholic liver disease (ALD) and accelerates liver aging, representing a progressive condition with limited therapeutic options. Recent evidence suggests that targeting hepatocellular senescence represents a promising therapeutic strategy, particularly through repurposing approved drugs capable of simultaneously ameliorating hepatic steatosis, inflammation, and liver aging. In this study, we screened reported anti-aging molecules and identified glucosamine (GlcN) as a candidate with the potential to mitigate both ALD and liver aging. In both acute and chronic mouse models of ALD, GlcN administration significantly reduced hepatic lipid accumulation, pro-inflammatory cytokine expression, and cellular senescence markers. Mechanistically, GlcN activated AMPK signaling, which subsequently suppressed the senescence-associated secretory phenotype (SASP) through modulation of the p38 MAPK pathway, and improved lipid metabolism by regulating the SREBP1/FAS and ACC pathways. These findings illustrate the multifaceted role of GlcN in ameliorating both cellular senescence and dysregulated lipid metabolism, thereby attenuating ALD progression. Our results support the repurposing of GlcN as a potential candidate for ALD and alcohol-associated liver aging.