Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related death, particularly in China, with limited diagnosic sensitivity and specificity. Circulating cell-free DNA (cfDNA) has emerged as a promising non-invasive biomarker. Eukaryotic Translation Initiation Factor 2C1 ( EIF2C1) , commonly used as a reference gene in digital PCR, reflects total cfDNA burden. This study aimed to evaluate the diagnostic value of plasma EIF2C1 -normalized cfDNA levels for HCC detection and to explore its association with disease severity and metastatic features at diagnosis.

Plasma samples from 101 HCC patients and 90 healthy controls were analyzed using Real-Time Quantitative PCR (RT-qPCR) to quantify EIF2C1 levels, employing two sets of primers and probes ( EIF2C1 -1 and EIF2C1 -2). Clinical data and tumor markers were collected to evaluate the association of EIF2C1 levels with disease severity and metastatic risk.

EIF2C1 levels were significantly elevated in HCC patients and correlated inversely with hepatic synthetic markers ,while positively associating with tumor progression indicators. Higher EIF2C1 expression was linked to advanced stage, cirrhosis, liver dysfunction, and metastasis. The combined models of EIF2C1 and alpha-fetoprotein (AFP) demonstrated enhanced discriminatory ability compared with individual markers ( EIF2C1 -1 + AFP: AUC=0.744, 95% CI: 0.642-0.845; EIF2C1 -2 + AFP: AUC=0.764, 95% CI: 0.662-0.866). Furthermore, elevated EIF2C1 levels were significantly associated with the presence of metastasis (OR=20.87, 95% CI: 5.13-84.92).

Plasma EIF2C1 levels show promise as a complementary diagnostic and risk-stratification biomarker in HCC. Its combination with AFP improves the identification of metastatic disease at diagnosis, potentially aiding initial clinical management .