Early detection of hepatocellular carcinoma (HCC) is a significant challenge due to the limited sensitivity of alpha-fetoprotein (AFP). This study aimed to assess serum-derived extracellular vesicle-encapsulated GULP PTB domain-containing engulfment adaptor 1 (EV-GULP1) as a novel, noninvasive biomarker for HCC detection and prognosis, leveraging the potential of tumor-specific molecules carried by small extracellular vesicles (EVs).

The study utilized both internal and external cohorts of HCC patients and controls. Small EVs were isolated from serum samples, then characterized and validated to confirm their identity. The expression levels of EV-GULP1 were quantified using quantitative reverse transcription polymerase chain reaction (qRT-PCR).

EV-GULP1 expression was found to be significantly higher in HCC patients, including those with early-stage disease, when compared to control groups. It demonstrated superior diagnostic accuracy over AFP, achieving an area under the curve (AUC) of 0.919, and was particularly effective in detecting AFP-negative cases. Furthermore, high EV-GULP1 expression correlated with worse overall and disease-free survival outcomes.

These findings highlight EV-GULP1 as a highly promising noninvasive biomarker for hepatocellular carcinoma. It offers improved diagnostic accuracy for early detection and better risk stratification for prognosis compared to the current standard, AFP.