This study aimed to assess serum-derived extracellular vesicle-encapsulated GULP PTB domain-containing engulfment adaptor 1 (<i>EV-GULP1</i>) as a novel, noninvasive biomarker for HCC detection and prognosis, leveraging the potential of tumor-specific molecules carried by small extracellular vesicles (EVs).<h4>Methods</h4>The study utilized both internal and external cohorts of HCC patients and controls. The gene discussed is GULP1; the disease is hepatocellular carcinoma.