In HepG2 and MHCC97 cells, MAPRE2 knockdown suppressed proliferation, invasion, and wound closure.<h4>Conclusion</h4>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, <i>in vivo</i>, transplant-cohort, and external prognostic validation. This evidence concerns the gene MAPRE2 and hepatocellular carcinoma.