Identification of PBMC senescence-associated transcriptional signature associated with Qizhu anti-cancer prescription response in hepatocellular carcinoma

The immunosuppressive tumor microenvironment contributes to the poor prognosis of hepatocellular carcinoma (HCC). The transcriptional profiles of senescence-associated genes (SAGs) in peripheral blood mononuclear cells (PBMCs) are enriched with pathways linked to immune dysfunction and may serve as noninvasive proxies of systemic immune status. This study aimed to identify and validate a PBMC-derived transcriptional signature enriched with SAGs as a noninvasive prognostic tool for HCC. We performed RNA sequencing on PBMCs from an orthotopic HCC mouse model treated with Qizhu anti-cancer prescription (QZACP). Senescence-associated differentially expressed genes (SAG-DEGs) were identified. Core candidates were screened by intersecting QZACP-modulated SAG-DEGs with predicted targets of blood-absorbed components through network pharmacology. The expression, prognostic value, and immune correlations of the core genes were validated using human HCC cohorts and public databases. We identified 587 SAG-DEGs enriched for immune pathways (e.g., interleukin-17 and tumor necrosis factor). Integration of transcriptomic and network pharmacology data identified five core genes. HSPA1A and ENPP2 were consistently upregulated in PBMCs and HCC tumor tissues. High ENPP2 expression was significantly associated with shorter overall survival, immunosuppressive tumor microenvironment features, and remained an independent prognostic factor in multivariate analysis. HSPA1A was consistently upregulated and correlated with immunosuppressive features. This study identified a PBMC-derived senescence-associated transcriptional signature associated with immunosuppression and poor HCC outcomes. ENPP2 emerged as a noninvasive independent prognostic biomarker, whereas HSPA1A was identified as a candidate biomarker associated with immunosuppression.