Adult hepatocyte identity is constructed throughout embryonic development and fine-tuned after birth. A multinodular network of transcription factors, along with pre-mRNA splicing regulators, define the transcriptome, which encodes the proteins needed to perform the complex metabolic and secretory functions of the mature liver. Transient hepatocellular dedifferentiation can occur as part of the regenerative mechanisms triggered in response to acute liver injury. However, persistent downregulation of key identity genes is now accepted as a strong determinant of organ dysfunction in chronic liver disease, a major global health burden. Therefore, the identification of core transcription factors and splicing regulators that preserve hepatocellular phenotype, and a thorough understanding of how these networks become disrupted in diseased hepatocytes, is of high clinical relevance. In this context, we review the key players in liver differentiation and discuss in detail critical factors, such as HNF4α, whose impairment mediates the breakdown of liver function. Moreover, we present compelling experimental evidence demonstrating that restoration of core transcription factor expression in a chronically injured liver can reset hepatocellular identity, improve function and ameliorate structural abnormalities. The possibility of correcting the phenotype of severely damaged and malfunctional livers may reveal new therapeutic opportunities for individuals with cirrhosis and advanced liver disease.

成人肝细胞身份是在整个胚胎发育过程中构建的，并在出生后进行微调。转录因子的多结节网络以及 pre-mRNA 剪接调节因子定义了转录组，它编码执行成熟肝脏的复杂代谢和分泌功能所需的蛋白质。短暂的肝细胞去分化可以作为响应急性肝损伤而触发的再生机制的一部分发生。然而，关键身份基因的持续下调现在被认为是慢性肝病器官功能障碍的重要决定因素，慢性肝病是全球主要的健康负担。因此，确定保留肝细胞表型的核心转录因子和剪接调节因子，并透彻了解这些网络如何在患病肝细胞中被破坏，具有很高的临床相关性。在此背景下，我们回顾了肝脏分化的关键参与者，并详细讨论了关键因素，例如 HNF4α，其损伤介导了肝功能的崩溃。此外，我们提供了令人信服的实验证据，证明在慢性损伤的肝脏中恢复核心转录因子表达可以重置肝细胞特性、改善功能和改善结构异常。纠正严重受损和功能障碍的肝脏表型的可能性可能为肝硬化和晚期肝病患者提供新的治疗机会。其损害介导肝功能的崩溃。此外，我们提供了令人信服的实验证据，证明在慢性损伤的肝脏中恢复核心转录因子表达可以重置肝细胞特性、改善功能和改善结构异常。纠正严重受损和功能障碍的肝脏表型的可能性可能为肝硬化和晚期肝病患者提供新的治疗机会。其损害介导肝功能的崩溃。此外，我们提供了令人信服的实验证据，证明在慢性损伤的肝脏中恢复核心转录因子表达可以重置肝细胞特性、改善功能和改善结构异常。纠正严重受损和功能障碍的肝脏表型的可能性可能为肝硬化和晚期肝病患者提供新的治疗机会。