The Fontan procedure is a reconstructive surgery for single-ventricle congenital heart disease. The procedure, often performed early in childhood, commonly results in multiple end-organ complications, including liver fibrosis or Fontan-associated liver disease (FALD). However, the underlying mechanisms of FALD are unknown and it is thought to be distinct from other forms of fibrotic liver disease. In a recent study, a transcriptomic and epigenomic atlas of human FALD was generated at the single-cell level, providing crucial insights into the pathogenesis of FALD.

Profound transcriptomic and epigenomic changes were observed in various cell types in livers from individuals with Fontan circulation (n = 4, Fontan operation at 2–3 years old and liver biopsy samples obtained as a teenager at 13–18 years old). Notably, central hepatocytes had the most substantial changes, including metabolic reprogramming. Changes in these central hepatocytes preceded activation of hepatic stellate cells and liver fibrosis. A network of ligand–receptor pairs involved in signalling from central hepatocytes to hepatic stellate cells were also identified, and in vitro studies demonstrated that activins A and B promote fibrotic activation.

Fontan手术是一种针对单心室先天性心脏病的重建手术。该手术通常在儿童早期进行，通常会导致多种终末器官并发症，包括肝纤维化或 Fontan 相关肝病 (FALD)。然而，FALD 的潜在机制尚不清楚，人们认为它与其他形式的纤维化肝病不同。在最近的一项研究中，在单细胞水平上生成了人类 FALD 的转录组和表观基因组图谱，为 FALD 的发病机制提供了重要的见解。

在患有 Fontan 循环的个体的肝脏中的各种细胞类型中观察到了深刻的转录组和表观基因组变化（ n = 4，Fontan 手术在 2-3 岁时进行，肝活检样本在 13-18 岁时获得）。值得注意的是，中央肝细胞发生了最实质性的变化，包括代谢重编程。这些中央肝细胞的变化先于肝星状细胞的激活和肝纤维化。还鉴定了参与从中央肝细胞到肝星状细胞信号传导的配体-受体对网络，体外研究表明激活素 A 和 B 促进纤维化激活。