肝细胞失去身份与酒精相关性肝炎（AH）中肝功能受损有关。在这种情况下，肝细胞去分化产生了具有胆肝（HB）表型、表达胆管和肝细胞标记以及显示不成熟特征的细胞。然而，肝细胞去分化的机制和在肝脏疾病中的影响尚不清楚。本研究定量和微切来自酒精相关性肝病（ALD）患者肝活检中的HB细胞和导管反应（DR）细胞，并评估小鼠肝损伤中CXCR4的肝细胞特异性过度表达或缺失以及CXCR4药理学抑制。还生成了患者来源和小鼠器官样联合体，以评估可塑性。我们发现，在失代偿性肝硬化和AH患者中，HB和DR细胞增加，但只有HB细胞与肝功能不佳和患者的结局相关。HB细胞的转录组分析显示胆管特异性基因的表达和肝细胞代谢的轻微降低。功能分析确定了参与肝细胞再编程、炎症、干性和癌症基因程序的通路。CXCR4途径在HB细胞中高度富集，与疾病严重程度和肝细胞去分化相关。在体外，CXCR4与胆管表型和肝细胞特征的丧失有关。肝过度表达CXCR4在慢性肝损伤中降低了肝细胞特异性基因表达谱，并促进了肝损伤。CXCR4的缺失或药物抑制改善了肝细胞去分化，并减少了DR和纤维化的进展。本研究展示了肝细胞去分化与AH中疾病进展和不良结局的关联。此外，HB细胞的转录组分析揭示CXCR4作为促进肝细胞-胆管再编程的新驱动因素和在AH中阻止肝细胞去分化的潜在治疗靶标。本研究还描述了肝细胞去分化与疾病严重程度和肝脏合成能力降低的关联，识别了CXCR4途径作为促进肝细胞去分化的驱动因素，并作为酒精相关性肝炎的治疗靶标。版权所有©2023 Elsevier B.V.

Loss of hepatocyte identity is associated with impaired liver function in alcohol-related hepatitis (AH). In this context, hepatocyte dedifferentiation gives rise to cells with a hepatobiliary (HB) phenotype expressing biliary and hepatocytes markers and showing immature features. However, the mechanisms and the impact of hepatocyte dedifferentiation in liver disease are poorly understood.HB cells and ductular reaction (DR) cells were quantified and microdissected from liver biopsies from patients with alcohol-related liver disease (ALD). Hepatocyte-specific overexpression or deletion of CXCR4, and CXCR4 pharmacological inhibition were assessed in mouse liver injury. Patient-derived and mouse organoids were generated to assess plasticity.Here we show that HB and DR cells are increased in patients with decompensated cirrhosis and AH, but only HB cells correlate with poor liver function and patients' outcome. Transcriptomic profiling of HB cells revealed the expression of biliary-specific genes and a mild reduction of hepatocyte metabolism. Functional analysis identified pathways involved in hepatocyte reprogramming, inflammation, stemness and cancer gene programs. CXCR4 pathway was highly enriched in HB cells, and correlated with disease severity and hepatocyte dedifferentiation. In vitro, CXCR4 was associated with biliary phenotype and loss of hepatocyte features. Liver overexpression of CXCR4 in chronic liver injury decreased hepatocyte specific gene expression profile and promoted liver injury. CXCR4 deletion or its pharmacological inhibition ameliorated hepatocyte dedifferentiation and reduced DR and fibrosis progression.This study shows the association of hepatocyte dedifferentiation with disease progression and poor outcome in AH. Moreover, the transcriptomic profiling of HB cells revealed CXCR4 as a new driver of hepatocyte-to-biliary reprogramming and as a potential therapeutic target to halt hepatocyte dedifferentiation in AH.Here we describe that hepatocyte dedifferentiation is associated with disease severity and a reduced synthetic capacity of the liver. Moreover, we identify the CXCR4 pathway as a driver of hepatocyte dedifferentiation and as a therapeutic target in alcohol-related hepatitis.Copyright © 2023. Published by Elsevier B.V.