Exploratory Study on the Prognostic Value and Biological Interpretability of PGF-Related H&E Pathomics Models in Hepatocellular Carcinoma

Abstract PURPOSE Placental growth factor (PGF) is implicated in hepatocellular carcinoma (HCC) progression, although its functional role remains unclear. This study aimed to develop a pathomics model for predicting PGF expression from H&E-stained HCC sections and investigate its prognostic relevance and molecular mechanisms. METHODS Retrospective analysis utilized H&E images and clinical data from TCGA and an external cohort. Prognostic significance of PGF was assessed via survival analysis. Image segmentation employed the OTSU algorithm, followed by PyRadiomics-based feature extraction. Key features were selected using mRMR and RFE algorithms, with a gradient boosting machine (GBM) model constructed for PGF prediction. Model performance was validated through ROC, calibration, and decision curve analyses. Prognostic stratification, Cox regression, and subgroup analyses were conducted for high/low pathomics score (PS) groups. Bioinformatics approaches identified differentially expressed genes (DEGs) and immune infiltration patterns. RESULTS PGF expression independently predicted poor HCC prognosis (HR=1.922, 95% CI:1.217-3.036,P=0.005). The pathomics model incorporating seven PGF-associated features demonstrated robust predictive performance (AUC=0.811; external validation AUC=0.740). High-PS patients exhibited significantly worse survival (HR=1.667, 95% CI:1.024–2.713, P=0.040). DEGs in high-PS subgroups showed enrichment in ribosome and coagulation pathways, accompanied by upregulated HBEGF (inflammation-related) and increased γδT cell infiltration. TP53mutations were prevalent (>20% mutation rate) in high-PS cases. CONCLUSION PGF serves as an independent prognostic biomarker in HCC. The developed pathomics model enables non-invasive PGF expression prediction through H&E image analysis. Mechanistically, PGF-associated molecular alterations involve inflammatory signaling, immune microenvironment remodeling, and frequent TP53 mutations, providing insights into HCC pathogenesis.