Abstract
The high rate of postoperative recurrence contributes to the poor outcome in hepatocellular carcinoma (HCC), and effective strategies for managing recurrence are currently lacking. Based on seven pairs of tumors and non-tumor adjacent tissues (NATs) proteomic datasets across five cancer types, this study systematically investigates the stratified and therapeutic value of tumors and NATs for tumor recurrence. NATs exhibited stable and irreplaceable independent prognostic capabilities for recurrence, complementing clinical indicators and tumor characteristics. In comparison to tumor tissues, NATs exhibit higher enrichment levels of recurrence-related proteins in pathways such as immunity, extracellular matrix, and angiogenesis. Taking HCC as an example, we identified SERPINH1 as a recurrent biomarker with drug-targeting potential that applied to both tumors and NATs and then validated them through independent immunohistochemistry cohorts and animal experiments. Patients with high SERPINH1 expression in both tumors and NATs have the highest 5-year recurrence rates, even among clinically low recurrence risk groups. Targeting SERPINH1 can effectively delay tumor occurrence and progression. This study highlights the significant importance of NATs in recurrence prediction and postoperative management, proposing a recurrence management strategy that focuses on both tumors and NATs. SERPINH1 emerges as a valuable biomarker and drug target for addressing postoperative recurrence in HCC.