Advances in electrochemical biosensor applications for liver cancer diagnosis: Focusing on AFP and GPC3.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, and the lack of effective early diagnostic methods remains a major challenge. Traditional imaging techniques and tissue biopsy still suffer from limitations in sensitivity, invasiveness, and cost. Although alpha-fetoprotein (AFP) remains the most widely used serum biomarker for HCC, its diagnostic performance is limited in early-stage and AFP-negative HCC. In contrast, glypican-3 (GPC3) shows higher tumor specificity and provides important complementary diagnostic value, particularly in AFP-negative HCC cases. Electrochemical biosensors have attracted increasing attention for AFP and GPC3 detection because of their rapid response, high sensitivity, low sample consumption, low cost, and easy miniaturization. This review summarizes recent advances in electrochemical biosensors for AFP and GPC3 detection, focusing on detection strategies, signal amplification approaches, interface engineering, and the roles of nanomaterials. Emerging trends, including microfluidic integration, flexible sensors, and point-of-care testing (POCT), are also discussed. In addition, this review highlights the expanding detection scope from AFP to GPC3 and other related biomarkers, especially for AFP-negative HCC. Finally, this review discusses current challenges, including standardization, antifouling capability, complex sample analysis, clinical validation, and portable system integration. Overall, AFP/GPC3 electrochemical biosensors are evolving toward multifunctional and clinically oriented diagnostic systems, showing strong potential for improving the early diagnosis and management of HCC.