Front Oncol. 2026 Aug 31;16:1956981. doi: 10.3389/fonc.2026.1956981. eCollection 2026.

ABSTRACT

INTRODUCTION: Maternal Embryonic Leucine Zipper Kinase (MELK) is a key regulator of the G2/M checkpoint and a recognized pan-cancer oncogene; however, its regulatory mechanisms and clinical significance in lung adenocarcinoma (LUAD) remain incompletely understood. This study aimed to investigate the molecular, prognostic, immune, and therapeutic relevance of MELK in LUAD.

METHODS: An integrated multi-omics approach was employed, incorporating gene-expression, survival, transcriptomic, immune-infiltration, regulatory-network, molecular docking, and molecular dynamics analyses. The potential MELK-associated ceRNA regulatory axis was investigated using bioinformatic approaches and subsequently evaluated by qRT-PCR in lung cancer cell lines. The therapeutic potential of candidate MELK-binding compounds was further explored using molecular docking and molecular dynamics simulations.

RESULTS: MELK was markedly overexpressed in LUAD (*log₂FC = 4.19) and was significantly associated with poor overall survival (HR = 1.63), with stronger prognostic associations in patients with stage I disease (HR = 2.07) and female smokers (HR = 1.50). MELK exhibited a strong positive correlation with FOXM1 (R = 0.834), supporting its coordinated involvement in the G2/M regulatory program. High MELK expression was associated with reduced effector immune-cell infiltration and increased enrichment of exhausted CD8⁺ T cells and regulatory T cells. Integrated regulatory analyses identified a putative **TMPO-AS1/hsa-let-7b-5p/MELK/FOXM1* ceRNA network characterized by increased TMPO-AS1 and MELK expression and reduced hsa-let-7b-5p expression. These expression patterns were further supported by qRT-PCR analysis in lung cancer cell lines. Molecular docking and molecular dynamics simulations identified *hesperidin* as a candidate MELK-binding compound with favorable predicted binding affinity and stable complex behavior.

CONCLUSION: These findings provide an integrated view of MELK dysregulation in LUAD, linking its G2/M-associated activity with post-transcriptional regulation, immune features, and potential therapeutic targeting. The *TMPO-AS1/hsa-let-7b-5p/MELK/FOXM1* axis may represent a promising molecular framework for understanding MELK-mediated LUAD progression and identifying prognostic biomarkers and therapeutic opportunities.

PMID:42741133 | PMC:PMC13572222 | DOI:10.3389/fonc.2026.1956981