Prognostic significance of the MELK/TMPO-AS1/hsa-let-7b-5p network in lung adenocarcinoma

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.

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.

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.

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.