PCTAIRE1 is a prognostic biomarker and complement-associated immunoregulatory target in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) remains a highly lethal malignancy with limited effective therapeutic targets. Although the PCTAIRE kinase subfamily has been implicated in cancer biology, its clinical relevance and functional significance in HCC remain poorly defined. In this study, we systematically investigated the expression pattern, prognostic value, biological functions, and immune-related role of PCTAIRE family members in HCC using multi-cohort transcriptomic, proteomic, single-cell, spatial transcriptomic, and experimental validation approaches. Among the three PCTAIRE family members, PCTAIRE1 showed the most consistent tumor-associated upregulation across independent HCC cohorts and was strongly associated with poor survival outcomes. Single-cell and spatial transcriptomic analyses further revealed that PCTAIRE1 expression was preferentially enriched in malignant HCC cells. Clinically, high PCTAIRE1 expression correlated with advanced tumor stage, higher histologic grade, vascular invasion, elevated AFP level, and unfavorable prognosis. Functional enrichment analyses linked PCTAIRE1-high tumors to cell-cycle activation, membrane-associated signaling, metabolic remodeling, and immune microenvironment alterations. Moreover, PCTAIRE1 expression was associated with immune infiltration remodeling, higher predicted immune escape, and poorer immunotherapy-related outcomes. Experimental validation confirmed that PCTAIRE1 was upregulated in HCC tissues and cell lines, while PCTAIRE1 knockdown suppressed tumor cell viability and xenograft tumor growth. Mechanistically, PCTAIRE1 depletion enhanced cytotoxic immune effector activity and altered Th2/Th17 polarization, and these effects were attenuated by complement inhibition with Compstatin. Collectively, our findings identify PCTAIRE1 as a clinically relevant oncogenic factor in HCC that links tumor-intrinsic progression with complement-associated immune regulation, suggesting its potential as a prognostic biomarker and therapeutic target.