ADAMTS3 as a promising novel biomarker for the diagnosis of hepatocellular carcinoma

Early diagnosis of hepatocellular carcinoma (HCC) still represents a significant challenge. The rising of obesity and non-viral liver disease associated HCC further limits the effectiveness of conventional screening approaches such as ultrasonography and alpha-fetoprotein (AFP) testing. In this context, the identification of potential effective biomarkers for rapid and precise diagnosis of HCC still represents an extremely important task. Here, we identify ADAMTS3 as a novel mechanistic serum biomarker for HCC that addresses this shifting etiological landscape. Transcriptome analysis of four independent cohorts–including HCC patients, individuals with obesity-or non-viral liver disease, and healthy controls– reveals four secreted proteins associated with HCC progression. Among them, ADAMTS3 demonstrates strong diagnostic performance by ROC (receiver operating characteristic) and LASSO (least absolute shrinkage and selection operator) analysis. High ADAMTS3 expression correlates with aggressive molecular signature, characterized by enhanced proliferative signaling, suppressed immune effector responses, and a reprogrammed immune microenvironment marked by reduced NK cell infiltration and increased accumulation of immunosuppressive tumor-associated macrophages, driven by extracellular matrix stiffening. Knockdown of ADAMTS3 in cell lines significantly reduced proliferation, and clonogenic potential. Reintroduction of ADAMTS3 partially rescued both phenotypes, further confirming its role in promoting HCC cell growth. Optical tweezer–based measurements further reveal reduced cell stiffness upon ADAMTS3 deficiency, highlighting its role in extracellular matrix (ECM) remodeling. Finally, to provide a simple strategy for HCC diagnosis based on this novel biomarker, we demonstrated a DNA origami-based SERS biosensor capable of detecting ADAMTS3 at 10 ^-11 M. Together, these findings identify ADAMTS3 as a mechanistic biomarker and demonstrate a translational sensing strategy for non-invasive HCC early screening.