MAPRE2 is associated with macrophage-enriched innate immune dysregulation and malignant phenotypes in hepatocellular...

Hepatocellular carcinoma (HCC) remains difficult to treat, and molecular determinants that link malignant behavior to the innate immune microenvironment are still needed.

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.

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.

MAPRE2 marks an aggressive HCC-associated molecular state coupled to macrophage-enriched innate immune dysregulation and may represent a candidate biomarker and therapeutic target that warrants rescue, in vivo, transplant-cohort, and external prognostic validation.