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Objective <p>Iron overload resulting from chronic alcohol consumption may aggravate liver damage, and the potential mechanisms involving ferritinophagic flux and the role of naturally occurring quercetin in alcohol-induced liver disease remain unclear.</p> Methods <p>Adult male C57BL/6J mice were iso-calorically pair-fed with ethanol-containing Lieber De Carli liquid diets according to a chronic-plus-binge ethanol feeding protocol with either quercetin (100&#xa0;mg/kg.bw) or iron-rich/limited treatment for 12&#xa0;weeks, and liver damage, as well as the underlying mechanisms of lysosome-dependent ferritinophagy, was explored, following the study of ethanol-incubated HepG2 cells with specific pharmacological reagents or gene regulation in vitro.</p> Results <p>Chronic-plus-binge ethanol feeding led to an increase in the hepatosomatic ratio, hepatic lipid accumulation and triglyceride (TG) content of the mice and induced the release of alanine aminotransferase (ALT), aspartate transaminase (AST), and serum TG levels, which were normalized partially by quercetin treatment or iron limitation but worsened by iron supplementation. Similar findings were observed in vitro. Moreover, quercetin intervention alleviated iron deposition, inhibited the upregulation of p62 and downregulation of nuclear receptor coactivator 4 (NCOA4) and microtubule-associated protein 1 light chain 3 (LC3)-II, and blocked the colocalization of NCOA4 and ferritin heavy chain and the nuclear translocation of forkhead box protein O1 (FOXO1) induced by ethanol. These effects were also observed when the cells were subjected to iron limitation but were abolished by iron supplementation, NCOA4 transfection, or AS1842856, a FOXO1 inhibitor.</p> Conclusion <p>Quercetin ameliorates secondary iron overload and subsequent liver damage caused by alcohol abuse by maintaining ferritinophagic flux and lysosome function via the FOXO1-TFEB NCOA4 signaling pathway.</p>

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The Protective Effects of Quercetin on Ferritinophagy in Alcoholic-Induced Liver Iron Overload

  • 期刊论文

  • 发表日期：

    2025年9月19日

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  • You Jin,
  • Hong-mei Zeng,
  • Chan Peng,
  • Jie Huang,
  • Shi-ting Huang,
  • Qian Zhang,
  • Hao-bin Yang,
  • Ping Yao,
  • Lan Ni

摘要

Objective

Iron overload resulting from chronic alcohol consumption may aggravate liver damage, and the potential mechanisms involving ferritinophagic flux and the role of naturally occurring quercetin in alcohol-induced liver disease remain unclear.

Methods

Adult male C57BL/6J mice were iso-calorically pair-fed with ethanol-containing Lieber De Carli liquid diets according to a chronic-plus-binge ethanol feeding protocol with either quercetin (100 mg/kg.bw) or iron-rich/limited treatment for 12 weeks, and liver damage, as well as the underlying mechanisms of lysosome-dependent ferritinophagy, was explored, following the study of ethanol-incubated HepG2 cells with specific pharmacological reagents or gene regulation in vitro.

Results

Chronic-plus-binge ethanol feeding led to an increase in the hepatosomatic ratio, hepatic lipid accumulation and triglyceride (TG) content of the mice and induced the release of alanine aminotransferase (ALT), aspartate transaminase (AST), and serum TG levels, which were normalized partially by quercetin treatment or iron limitation but worsened by iron supplementation. Similar findings were observed in vitro. Moreover, quercetin intervention alleviated iron deposition, inhibited the upregulation of p62 and downregulation of nuclear receptor coactivator 4 (NCOA4) and microtubule-associated protein 1 light chain 3 (LC3)-II, and blocked the colocalization of NCOA4 and ferritin heavy chain and the nuclear translocation of forkhead box protein O1 (FOXO1) induced by ethanol. These effects were also observed when the cells were subjected to iron limitation but were abolished by iron supplementation, NCOA4 transfection, or AS1842856, a FOXO1 inhibitor.

Conclusion

Quercetin ameliorates secondary iron overload and subsequent liver damage caused by alcohol abuse by maintaining ferritinophagic flux and lysosome function via the FOXO1-TFEB NCOA4 signaling pathway.