The oncogenic and tumor suppressor roles of lnc‑MAPKAPK5‑AS1 in multiple cancers suggest its complexity in modulating cancer progression. The expression and promoter methylation level of lnc‑MAPKAPK5‑AS1 in hepatocellular carcinoma (HCC) was investigated through data mining from The Cancer Genome Atlas and Gene Expression Omnibus and its significance in prognosis and immunity was explored. lnc‑MAPKAPK5‑AS1 was co‑expressed with its protein‑coding gene MAPKAPK5 in HCC and exhibited upregulation in HCC tissues as a result of hypomethylation of its promoter region. High expression of lnc‑MAPKAPK5‑AS1 was associated with poor prognosis. Enrichment analysis revealed that lnc‑MAPKAPK5‑AS1 is involved in immune and metabolic‑related pathways. Changes in the expression of lnc‑MAPKAPK5‑AS1 affected plasma cells, T cells CD4+ memory resting, NK cells, macrophages M0/M1, and mast cells resting in the tumor microenvironment. lnc‑MAPKAPK5‑AS1 was found to correlate with multiple immune checkpoints. Analysis of the Sangerbox database revealed positive relationships between expression of lnc‑MAPKAPK5‑AS1, tumor mutational burden and microsatellite instability, which suggested that immunotherapy may be effective in tumors with high expression of lnc‑MAPKAPK5‑AS1. The expression of lnc‑MAPKAPK5‑AS1 was verified to indicate sensitivity to 16 common targeted drugs. Immunohistochemistry confirmed the expression of MAPKAPK5 protein in HCC and its prognostic significance. Weighted gene co‑expression network analysis was applied to identify hub genes related to both immunoreactive score and gene expression. These results revealed that lnc‑MAPKAPK5‑AS1 may be involved in the occurrence and development of HCC as an oncogene and may represent a potential therapeutic target through modulating the substance metabolism and immune response.

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