Precision therapy and prognostic assessment are crucial for improving the quality of life of patients with lung cancer. While NSUN2-mediated m⁵C RNA methylation is involved in multiple malignancies, the role of its downstream target MMP14 in lung adenocarcinoma remains undefined.

Using the A549 cell line as the research object, we established a stable NSUN2 knockdown model. Differentially expressed gene MMP14 was identified through RNA-seq, and its expression was validated by quantitative real-time polymerase chain reaction (RT-qPCR). Combined with The Cancer Genome Atlas (TCGA) and multi-database integrated analysis, we thoroughly elucidated the molecular regulatory mechanisms (focusing on RNA methylation-related pathways) and clinical value of MMP14 in LUAD.

Our findings demonstrate that MMP14 is overexpressed in LUAD and multiple other malignancies, and that its elevated expression is significantly associated with poor prognosis and advanced tumor stage. In LUAD, MMP14 RNA methylation levels are positively correlated with mRNA expression, while DNA promoter methylation is closely linked to tumor progression and lymph node metastasis. MMP14 expression is regulated by NSUN2, a key m⁵C methyltransferase, and functionally participates in diverse tumor-associated biological processes. Notably, MMP14 expression correlates with immune cell infiltration, including macrophages and T cells, as well as with immune checkpoint molecules such as PD-1 and PD-L1, highlighting its potential role in shaping the tumor immune microenvironment.

MMP14, a key NSUN2-regulated molecule in LUAD, represents a potential target for precision diagnosis and therapy and may provide new insights into improving overall survival in LUAD.