Background and AimsIron overload, oxidative stress and ferroptosis are associated with liver injury in alcohol‐associated liver disease (ALD), however, the crosstalk among these regulatory pathways in ALD development is unclear.MethodsALD mouse model and general control of amino acid synthesis 5 like 1 (GCN5L1) liver knockout mice were generated to investigate the role of GCN5L1 in ALD development. Proteomic screening tests were performed to identify the key factors mediating GCN5L1 loss‐induced ALD.ResultsGene Expression Omnibus data set analysis indicates that GCN5L1 expression is negatively associated with ALD progression. GCN5L1 hepatic knockout mice develop severe liver injury and lipid accumulation when fed an alcohol diet. Screening tests identified that GCN5L1 targeted the mitochondrial iron transporter CISD1 to regulate mitochondrial iron homeostasis in ethanol‐induced ferroptosis. GCN5L1‐modulated CISD1 acetylation and activity were crucial for iron accumulation and ferroptosis in response to alcohol exposure.ConclusionPharmaceutical modulation of CISD1 activity is critical for cellular iron homeostasis and ethanol‐induced ferroptosis. The GCN5L1/CISD1 axis is crucial for oxidative stress and ethanol‐induced ferroptosis in ALD and is a promising avenue for novel therapeutic strategies.

中文翻译：

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GCN5L1 缺失会通过铁死亡激活加剧酒精性肝病的损害

背景和目的铁超载、氧化应激和铁死亡与酒精相关性肝病 (ALD) 的肝损伤有关，然而，这些调节途径在 ALD 发展中的串扰尚不清楚。 方法 ALD 小鼠模型和氨基酸合成的一般控制 5生成肝脏敲除小鼠 GCN5L1（GCN5L1）以研究 GCN5L1 在 ALD 发展中的作用。进行蛋白质组筛选测试以确定介导 GCN5L1 缺失诱导 ALD 的关键因素。结果基因表达综合数据集分析表明 GCN5L1 表达与 ALD 进展呈负相关。 GCN5L1 肝基因敲除小鼠在喂食酒精饮食时会出现严重的肝损伤和脂质堆积。筛选测试发现，GCN5L1 靶向线粒体铁转运蛋白 CISD1，以调节乙醇诱导的铁死亡中的线粒体铁稳态。 GCN5L1 调节的 CISD1 乙酰化和活性对于酒精暴露引起的铁积累和铁死亡至关重要。结论 CISD1 活性的药物调节对于细胞铁稳态和乙醇诱导的铁死亡至关重要。 GCN5L1/CISD1 轴对于 ALD 中的氧化应激和乙醇诱导的铁死亡至关重要，是新治疗策略的一个有前途的途径。