Oncogenic Signaling Activation and Potential Biomarkers in Congestive Hepatopathy Revealed by Proteomic Analysis

ABSTRACT Aim Fontan surgery improves outcomes in univentricular heart disease; however, some patients develop severe Fontan‐associated liver disease (FALD). Even during adolescence, hepatocellular carcinoma occurs in some patients with FALD, although the mechanism remains unclear. In this study, we conducted proteomic analyses of liver tissues obtained using laser capture microdissection (LCM) and serum samples to investigate FALD‐related peripheral liver oncogenic factors and explore potential biomarkers. Methods Ten‐week‐old mice underwent sham surgery, and age‐matched mice underwent partial ligation of the suprahepatic inferior vena cava as a congestive hepatopathy (CH) model. Control liver (CL) and serum were collected from the control models, whereas peripheral congestive liver (PCL) and serum were obtained from the CH models. LCM‐isolated liver and serum samples were subjected to qualitative and quantitative proteomic analyses. Differentially expressed proteins (DEPs) were identified by mass spectrometry. Results We identified 3904 hepatic proteins and 2947 serum proteins. Cancer‐related proteins were upregulated in PCL, whereas hepatoprotective proteins were reduced compared with those in CL. Enrichment analysis revealed the upregulation of oncogenic signaling pathways in PCL. Twenty DEPs (e.g., transforming growth factor‐beta‐induced protein ig‐h3, complement C1q subcomponent subunit A, and Dickkopf‐related protein 3) were concurrently increased in PCL and serum of the CH models. Conclusions PCL upregulated oncogenic proteins and activated oncogenic signaling pathways. DEPs detectable in the liver and serum indicate potential FALD biomarkers. These findings offer insights into the pathophysiology of FALD and hepatocarcinogenesis and support the development of novel diagnostic and therapeutic strategies.