Multi-omics investigation into the role of PTK7 as a driver of liver fibrosis.

Liver fibrosis is a critical stage in the progression of chronic liver disease to cirrhosis, and effective antifibrotic targets remain lacking. This study aims to investigate the association between protein tyrosine kinase 7 (PTK7) and liver fibrosis through multi-omics analyses, explore its potential role in hepatic stellate cell activation, and evaluate the value of circulating PTK7 as a candidate biomarker for assessing liver fibrosis severity. Genome-wide association study (GWAS) summary statistics, cis-expression quantitative trait locus (cis-eQTL), and plasma protein quantitative trait locus (pQTL) datasets were integrated to identify candidate genes associated with liver fibrosis. Candidate genes were further validated using multiple machine-learning models in three independent Gene Expression Omnibus (GEO) cohorts (GSE84044, GSE25097, and GSE49541). Human and murine liver single-cell transcriptomic datasets were analyzed to characterize the expression profile of PTK7. In an exploratory clinical cohort, plasma PTK7 levels were measured by enzyme-linked immunosorbent assay (ELISA), and PTK7 expression was evaluated in a carbon tetrachloride (CCl4)-induced mouse model of liver fibrosis. In LX-2 cells, PTK7 was silenced to assess changes in β-catenin and fibrosis-related proteins, followed by intervention with SKL2001. Molecular docking and molecular dynamics simulations were performed to evaluate the potential interaction between PTK7 and β-catenin. A total of 18 candidate genes were identified, among which PTK7 consistently showed upregulated expression in fibrotic liver tissues across multiple datasets. Single-cell transcriptomic analysis revealed enriched PTK7 expression in Kupffer cells and fibroblast-related populations. Plasma PTK7 levels were significantly elevated in patients with liver fibrosis and were positively correlated with liver stiffness measurements. In activated LX-2 cells, PTK7 knockdown reduced the expression levels of collagen type I alpha 1 chain (COL1A1), alpha-smooth muscle actin (α-SMA), and β-catenin. Furthermore, rescue experiments using SKL2001 supported the involvement of β-catenin-related signaling pathways in PTK7-mediated profibrotic effects. Computational analyses suggested a stable interaction pattern between PTK7 and β-catenin. PTK7 is closely associated with liver fibrosis at both multi-omics and transcriptomic levels, may participate in hepatic stellate cell activation, and may be associated with β-catenin-related signaling pathways. Circulating PTK7 may serve as a candidate biomarker for reflecting the severity of liver fibrosis; however, further validation in larger clinical cohorts is warranted.