Alcohol-Associated Hepatocarcinogenesis: Wnt/β-Catenin in Action.

IF 4.7 2区医学 Q1 PATHOLOGY

American Journal of Pathology Pub Date : 2025-05-09 DOI:10.1016/j.ajpath.2025.04.016

Yuhua Xue, Tian Tian, Melak Ottallah, Mahfuza Mannan, Joshua Barkin, Brady Jin-Smith, Liya Pi

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引用次数: 0

Abstract

Chronic alcohol consumption is a leading global health concern, primarily due to its deleterious effects on liver function and its well-established association with hepatocellular carcinoma (HCC). Alcohol-related liver disease (ALD) encompasses a continuum-from reversible hepatic steatosis and steatohepatitis through progressive fibrosis and cirrhosis to overt HCC. Accumulating studies have revealed that the Wnt/β-catenin signaling pathway is an essential regulator in ALD pathogenesis, orchestrating diverse molecular, immunological, and epigenetic processes. Aberrant β-catenin activity disrupts redox homeostasis, promotes chronic inflammation, drives extracellular matrix (ECM) remodeling, and alters hepatocyte fate decisions, thereby creating a microenvironment that is highly conducive to carcinogenesis. Here, we provide a systemic review of the significant function of Wnt/β-catenin signaling in ALD, emphasizing its regulatory impact on liver fat accumulation, its inflammatory role in steatohepatitis, its involvement in fibrogenesis, and its tumor-promoting effects in alcohol-related HCC. In addition, we explore emerging therapeutic strategies-including direct Wnt modulators, combinatory therapeutics, and precision medicine approaches-that offer potential for early identification and tailored therapy of ALD.

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酒精相关肝癌的发生：Wnt/β-连环蛋白的作用

慢性饮酒是一个主要的全球健康问题，主要是由于其对肝功能的有害影响及其与肝细胞癌（HCC）的明确关联。酒精相关性肝病（ALD）包括一个连续的过程——从可逆性肝脂肪变性和脂肪性肝炎，到进行性纤维化和肝硬化，再到显性HCC。越来越多的研究表明，Wnt/β-catenin信号通路是ALD发病的重要调节因子，协调多种分子、免疫和表观遗传过程。异常的β-连环蛋白活性破坏氧化还原稳态，促进慢性炎症，驱动细胞外基质（ECM）重塑，并改变肝细胞命运决定，从而创造一个高度有利于致癌的微环境。在这里，我们对Wnt/β-catenin信号在ALD中的重要功能进行了系统回顾，强调了其对肝脏脂肪积累的调节作用，在脂肪性肝炎中的炎症作用，在纤维发生中的参与，以及在酒精相关性HCC中的促肿瘤作用。此外，我们还探索了新兴的治疗策略，包括直接Wnt调节剂、联合治疗和精准医学方法，这些方法为ALD的早期识别和定制治疗提供了潜力。

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来源期刊

American Journal of Pathology 医学-病理学

CiteScore

11.40

自引率

0.00%

发文量

178

审稿时长

30 days

期刊介绍： The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.