Integrated spatial and single-cell transcriptomics reveals RPL8 as a prognostic biomarker and therapeutic target in hepatocellular carcinoma

<h4>Background & aims</h4>Ribosomal protein L8 (RPL8) is up-regulated in hepatocellular carcinoma (HCC), yet its clinical value and microenvironment role remain unclear.<h4>Methods</h4>Multi-omics (TCGA, CPTAC), scRNA-seq (GSE146115) and spatial transcriptomics were integrated; function was tested by RPL8 knockdown, proliferation/migration assays and drug-sensitivity screens.<h4>Results</h4>RPL8 mRNA/protein were markedly elevated (p < 0.001) with AUC 0.95 for diagnosis. High RPL8 independently predicted shorter overall (HR 1.42) and disease-specific survival (HR 1.35). Mechanistically, RPL8 co-activated MYC/G2M signaling, rewired glutathione metabolism and correlated with cell-cycle/DNA-repair scores (p < 0.001). scRNA-seq showed selective RPL8 enrichment in malignant hepatocytes and exhausted CD8⁺T cells; spatial maps revealed tumor-confined expression inversely linked to immune infiltration (p < 0.01). Silencing RPL8 suppressed proliferation, migration and glutathione synthesis (p < 0.001), while sensitizing cells to sirolimus and sclareol (p < 0.05).<h4>Conclusions</h4>RPL8 drives HCC progression and immune evasion, qualifying it as a diagnostic biomarker and therapeutic target.