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Background: Hepatocellular carcinoma (HCC) remains difficult to treat, and molecular determinants that link malignant behavior to the innate immune microenvironment are still needed. Methods: We integrated two-sample Mendelian randomization using cis-eQTL and cis-pQTL instruments with tumor transcriptomics, immune deconvolution, DNA methylation analyses, single-cell RNA sequencing, and loss-of-function assays to prioritize and characterize MAPRE2 in HCC. Results: Multi-omics Mendelian randomization identified MAPRE2 as a concordant risk-increasing candidate across transcript and protein layers. MAPRE2 was overexpressed in tumors and associated with worse overall survival. MAPRE2-high tumors were enriched for complement activation, TNFA signaling via NF-kB, interferon gamma response, extracellular matrix remodeling, and epithelial-mesenchymal transition, and showed stronger macrophage-, neutrophil-, and dendritic-cell-related signatures together with lower immunophenoscores, consistent with an inflamed but immunosuppressed innate immune microenvironment. Single-cell analysis showed multicompartment expression of MAPRE2, and virtual knockout implicated metabolic, adhesion, and extracellular programs. DNA methylation was associated with MAPRE2 expression and outcome, whereas recurrent high-level somatic amplification was rare. In HepG2 and MHCC97 cells, MAPRE2 knockdown suppressed proliferation, invasion, and wound closure. Conclusion: , transplant-cohort, and external prognostic validation.
An et al. (2026) studied this question.