OBJECTIVES: This study investigated the expression, clinical relevance, and functional role of signal sequence receptor 1 (SSR1) in liver hepatocellular carcinoma (LIHC). SSR1's potential as a diagnostic marker and its impact on tumor progression was assessed through multi-platform data analysis and in vitro functional assays. METHODOLOGY: Expression data from The Cancer Genome Atlas (TCGA), UALCAN, Oncomine, TIMER2.0, and Human Protein Atlas (HPA) were analyzed to assess SSR1 mRNA and protein expression in LIHC. Clinical correlations with tumor stage, race, gender, age, weight, and nodal metastasis were examined using UALCAN. Promoter methylation, mutation frequency, and prognostic significance were evaluated using UALCAN and OncoDB. Gene set enrichment analysis (GSEA) was conducted to identify pathways enriched in high SSR1 expression. Finally, real-time quantitative polymerase chain reaction (RT-qPCR), proliferation, colony formation, and wound healing assays were performed in QGY-7703 cell lines to validate the SSR1 function. RESULTS: SSR1 was significantly upregulated in LIHC tissues across multiple databases. Promoter hypomethylation was identified as a potential mechanism for this upregulation. High SSR1 expression correlated with worse overall survival and advanced tumor stages. Functional assays revealed that SSR1, SSR2, and SSR3 knockdown in LIHC cells significantly reduced cell proliferation and colony formation while enhancing migratory capacity. CONCLUSION: SSR1 was overexpressed in LIHC and is associated with poor prognosis. It plays a critical role in promoting LIHC cell proliferation and survival, suggesting its potential as a diagnostic marker and therapeutic target.