Tongtong Pan, Yujuan Shen, Ting Li, Fangfang Yi, Shijia Wu, Yilun Huang, Huadong Zhang, Qiongying Zhang, Yongping Chen, Dazhi Chen
Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China.
Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China; Huzhou Key Laboratory of Precision Medicine Research and Translation for Infectious Diseases, Huzhou Central Hospital, Wuxing District, Huzhou 313000, China.
Genomics. 2025 Mar;117(2):111009. doi: 10.1016/j.ygeno.2025.111009. Epub 2025 Jan 27.
Ferroptosis is associated with alcoholic hepatitis (AH); however, the underlying mechanisms remain unclear.
Changes in iron content and oxidative stress in AH patients and in vivo and in vitro models were analyzed. Iron homeostasis pathways in the livers of patients with AH were investigated using RNA sequencing. AH-associated ferroptosis-related genes (FRGs) were identified using weighted gene co-expression network analysis. Hub genes were identified using machine learning methods, and their diagnostic potential for AH was assessed. The correlation between FRGs and the immune microenvironment was analyzed, and the underlying regulatory mechanism was explored. FRG expression was validated in clinical samples and in vitro and in vivo models. The role of FRGs in AH-related ferroptosis was explored through gene-silencing experiments.
Significant iron deposits and oxidative stress were detected in clinical samples and in vivo and in vitro AH models. Bioinformatics identified GCLC, NQO1, and ULK1 as key FRGs linked to the immune microenvironment and AH-related pathogenic genes. A nomogram based on these FRGs accurately assessed AH risk, as validated using the calibration curve. A regulatory network involving 154 miRNAs and 136 transcription factors was mapped for FRGs. In AH patients, NQO1 was upregulated in the liver, whereas GCLC and ULK1 were downregulated. Silencing GCLC and ULK1 reduced cell viability and increased oxidative stress and ferroptosis, whereas silencing NQO1 had the opposite effect.
Therefore, GCLC, NQO1, and ULK1 are key AH-related FRGs, potentially serving as targets for diagnosing and treating AH.
铁死亡与酒精性肝炎（AH）相关；然而，其潜在机制仍不清楚。
分析了AH患者以及体内和体外模型中铁含量和氧化应激的变化。使用RNA测序研究了AH患者肝脏中的铁稳态途径。使用加权基因共表达网络分析鉴定了与AH相关的铁死亡相关基因（FRG）。使用机器学习方法鉴定了枢纽基因，并评估了它们对AH的诊断潜力。分析了FRG与免疫微环境之间的相关性，并探索了潜在的调控机制。在临床样本以及体内和体外模型中验证了FRG的表达。通过基因沉默实验探索了FRG在AH相关铁死亡中的作用。
在临床样本以及体内和体外AH模型中检测到明显的铁沉积和氧化应激。生物信息学将GCLC、NQO1和ULK1鉴定为与免疫微环境和AH相关致病基因相关的关键FRG。基于这些FRG的列线图准确评估了AH风险，校准曲线验证了这一点。为FRG绘制了一个涉及154个miRNA和136个转录因子的调控网络。在AH患者中，肝脏中NQO1上调，而GCLC和ULK1下调。沉默GCLC和ULK1降低了细胞活力，增加了氧化应激和铁死亡，而沉默NQO1则产生相反的效果。
因此，GCLC、NQO1和ULK1是与AH相关的关键FRG，可能作为诊断和治疗AH的靶点。
