Leveraging data‐independent acquisition mass spectrometry coupled with machine learning, we uncovered potential vesicular protein biomarker signatures (KNG1, F11, KLKB1, CAPNS1, CDH1, CPN2, NME2) capable of distinguishing HBV‐HCC from CHB, LC, and non‐HCC conditions. The gene discussed is F11; the disease is hepatocellular carcinoma.