PBMC Senescence-Associated Transcriptional Signatures Identify HSPA1A and ENPP2 as Prognostic Biomarkers for Hepatocellular Carcinoma
Background: The immunosuppressive tumor microenvironment contributes to the poor prognosis of hepatocellular carcinoma (HCC). Senescence-associated genes (SAGs) in peripheral blood mononuclear cells (PBMCs) may reflect systemic immune status. This study aimed to identify non-invasive prognostic SAG biomarkers for HCC using a drug target-informed strategy.Methods: We performed RNA-seq on PBMCs from an orthotopic HCC mouse model treated with Qizhu anti-cancer prescription (QZACP). Senescence-associated differentially expressed genes (CS-DEGs) were identified and analyzed. Core candidates were screened by intersecting QZACP-modulated CS-DEGs with predicted targets of its blood-absorbed components via network pharmacology. Expression, prognostic value, and immune correlations of core genes were validated in human HCC cohorts and public databases.Results: We identified 587 CS-DEGs enriched in immune pathways (e.g., IL-17, TNF). Integration of transcriptomic and network pharmacology data pinpointed five core genes. Among them, HSPA1A and ENPP2 were consistently upregulated in both PBMCs and tumor tissues of HCC patients. High expression of either gene was significantly associated with advanced stage, shorter overall survival, and an immunosuppressive tumor microenvironment.Conclusion: This study identifies HSPA1A and ENPP2 as novel, non-invasive prognostic biomarkers for HCC, derived from a PBMC senescence signature. This signature, informed by an effective therapy's targets, strongly correlates with immunosuppression and poor outcomes, offering new avenues for patient stratification.