CD2AP is a disulfidptosis modulator and prognostic biomarker in hepatocellular carcinoma

CD2-associated protein (CD2AP) is an adapter protein that stabilizes the actin cytoskeleton and is closely linked to disulfidptosis. However, its functional role in hepatocellular carcinoma (HCC) progression and disulfidptosis remains undefined. Herein, pan-cancer multiomics analyses were performed on 33 malignancies from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) cohorts to evaluate CD2AP expression patterns, prognostic significance, and interactions with the tumor immune microenvironment. Clinical validation was performed using 70 HCC specimens, with qRT-PCR analysis and survival assessments. CD2AP expression was significantly elevated in tumor tissues across multiple cancer types and correlated with poor survival outcomes. In tumor tissues, high CD2AP expression positively correlated with the expression of immune checkpoints, including HAVCR2, CTLA4, CD274, TIGIT, and PDCD1. Additionally, qRT-PCR analysis of 70 HCC patients in our cohort confirmed a marked upregulation of CD2AP in HCC tumor tissues. Specifically, Kaplan-Meier analysis further revealed that high CD2AP expression was associated with reduced overall survival and recurrence-free survival in our HCC cohort. Functional experiments demonstrated that CD2AP silencing inhibited HCC cell proliferation and enhanced disulfidptosis susceptibility in SLC7A11-high cells, likely via NADPH depletion and actin network disruption. In conclusion, our findings indicate that CD2AP functions as an oncogene in HCC, promoting tumor progression by regulating disulfidptosis. This study provides novel insights into CD2AP as a potential prognostic biomarker and therapeutic target for HCC.