APCS is a redox-sensitive regulator linking miR-24-2-5p to AMPK suppression and alcohol-induced hepatic steatosis

Chronic alcohol consumption promotes hepatic steatosis, a key feature of alcohol-associated liver disease (ALD), yet the signaling mechanisms linking oxidative stress to lipid dysregulation remain incompletely understood. Here, we identify amyloid P component (APCS) as a previously unrecognized, alcohol-repressed hepatoprotective factor that is consistently suppressed during ALD progression. Transcriptomic, biochemical, and histological analyses revealed markedly reduced APCS expression in the livers of ALD patients and alcohol-fed mice, as well as in ethanol-treated hepatocytes. Functional studies demonstrated that liver-specific APCS deficiency increases susceptibility to alcohol-induced hepatic steatosis in vivo and promotes lipid accumulation in hepatocytes. Mechanistically, we identified miR-24-2-5p as an alcohol-inducible microRNA that directly targets Apcs. Manipulation of miR-24-2-5p reciprocally regulated APCS expression and hepatocellular lipid accumulation. Further analyses revealed that the miR-24-2-5p/APCS axis modulates AMPK activity, potentially through regulation of mitochondrial function, cellular redox homeostasis, and cAMP-associated signaling pathways. APCS depletion reduced AMPK phosphorylation and activity, whereas inhibition of miR-24-2-5p restored AMPK signaling. Pharmacological modulation confirmed AMPK as a critical downstream effector mediating the lipogenic effects associated with APCS deficiency. Importantly, antioxidant intervention with N-acetylcysteine (NAC) attenuated alcohol-induced miR-24-2-5p upregulation, restored APCS expression, and reactivated AMPK both in vivo and in vitro, whereas pro-oxidant stimuli recapitulated these regulatory effects. Collectively, these findings define an oxidative stress-driven miR-24-2-5p/APCS/AMPK regulatory axis that governs alcohol-induced hepatic steatosis and highlight a potential therapeutic target for ALD.