A significant challenge in improving outcomes for hepatocellular carcinoma (HCC) patients is the scarcity of reliable prognostic markers and predictive tools. Chondroitin Sulfate Proteoglycan 4 (CSPG4) has shown potential as an oncogenic driver in various cancers, but its role in HCC is largely unexplored.

CSPG4 expression was analyzed using The Cancer Genome Atlas data and two independent cohorts of HCC patients who underwent curative-intent hepatectomy (n = 153 and n = 112). Immunohistochemistry was used to assess CSPG4 expression. The optimal cutoff value for CSPG4 H-score was determined by receiver operating characteristic (ROC) curve analysis combined with the Youden index. Survival curves were plotted via the Kaplan-Meier method, and differences in survival rates were compared using the log-rank test. Multivariate analyses were utilized to determine the prognostic significance of CSPG4, both independently and in conjunction with established clinical parameters. In vitro studies using CSPG4 knockdown or recombinant CSPG4 protein treatment in HCC cell lines were conducted, with cell proliferation, migration and invasion assessed by CCK-8, wound healing and transwell assays.

The expression of CSPG4 was significantly upregulated in HCC tissues compared to adjacent normal liver tissues. Elevated levels of CSPG4 were associated with more severe clinical and pathological characteristics, as well as reduced overall survival (OS) and shorter progression-free survival (PFS) across both study groups. In vitro experiments demonstrated that CSPG4 knockdown suppressed proliferation, migration and invasion of HCC cells, while recombinant CSPG4 protein treatment promoted cell proliferation in a dose-dependent manner. High CSPG4 expression was an independent risk factor for OS in HCC patients after resection (hazard ratio 2.577, 95% confidence interval [CI]: 1.564–4.246, P < 0.001). The combined predictive model incorporating CSPG4 expression with clinical parameters, especially tumor size and microvascular invasion achieved a C-index of 0.811 (95% CI: 0.742–0.881) for OS prediction, which was significantly superior to traditional staging systems.

CSPG4 overexpression serves as an oncogenic driver and independent predictor of poor survival in HCC. Combining CSPG4 expression with established clinical variables presents a more precise risk assessment tool for individuals with HCC after hepatectomy, offering new insights for personalized treatment strategies and outcome prediction in HCC.