Integrative Multi-Omics Analysis Reveals HNRNPLL as a Potential Biomarker Associated with Hepatocellular Carcinoma Progression

Background: Heterogeneous nuclear ribonucleoprotein L-like (HNRNPLL) is an RNA-binding protein involved in alternative splicing and immune regulation; however, its role in liver hepatocellular carcinoma (LIHC) remains unclear. Methods: We performed integrative multi-omics analyses using data from TCGA, GEO, and the Human Protein Atlas to evaluate the expression patterns, prognostic value, and potential biological functions of HNRNPLL. Functional enrichment and immune-related analyses were conducted to explore associated pathways. Experimental validation was performed in LIHC cell lines using Western blotting, RT-qPCR, CCK-8, colony formation, and Transwell assays, along with a xenograft mouse model. Results: HNRNPLL was significantly upregulated in LIHC at both transcriptomic and proteomic levels and was associated with advanced clinicopathological features and poor overall survival. Multivariate Cox regression analysis identified HNRNPLL as an independent prognostic factor. Enrichment analyses suggested that HNRNPLL-related genes are mainly involved in cell cycle regulation, mitotic progression, epithelial–mesenchymal transition, and immune-related pathways. In addition, HNRNPLL expression was correlated with immune cell infiltration, tumor mutational burden, microsatellite instability, ferroptosis-related genes, and m6A methylation regulators. Functional experiments demonstrated that HNRNPLL knockdown suppressed proliferation, migration, and invasion of liver cancer cells and inhibited tumor growth in vivo. Conclusions: These findings suggest that HNRNPLL may act as a potential regulator of LIHC progression and is associated with tumor-related biological processes and immune features. HNRNPLL may serve as a candidate biomarker for prognosis and a potential therapeutic target in LIHC, although further mechanistic studies are required.