MiR-4788 promotes NSCLC progression by targeting DLG5 to enhance mitochondrial function

BACKGROUND/OBJECTIVES: Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide. Although microRNAs (miRNAs) are known to play crucial roles in tumor progression, the biological function and mechanistic role of miR-4788 in NSCLC remain undefined. This study investigates the role and mechanism of miR-4788 in NSCLC proliferation and metastasis. METHODS: miR-4788 expression and its prognostic significance were analyzed using The Cancer Genome Atlas (TCGA) data. In vitro assays were conducted in NSCLC cell lines transfected with miR-4788 mimics, DLG5 siRNA, or a 3'-UTR-truncated DLG5 overexpression plasmid. In vivo functional validation was performed in zebrafish and murine xenograft models. Functional assays included assessments of cell viability (CCK-8), proliferation (EdU incorporation, colony formation), cell cycle distribution, migration/invasion (wound healing, Transwell), and mitochondrial function (ATP, MMP, ROS, mitophagy markers). A dual-luciferase reporter assay was used to confirm DLG5 as a direct miR-4788 target, and rescue experiments were conducted to validate its downstream role. RESULTS: miR-4788 was significantly upregulated in NSCLC tissues and was associated with a lower disease-specific survival rate. Its overexpression in vitro and in vivo promoted the proliferation, migration, and invasion of non-small cell lung cancer cells. This oncogenic effect was accompanied by enhanced mitochondrial function, evidenced by increased mitochondrial membrane potential, ATP production, and reactive oxygen species (ROS) levels, along with suppression of mitophagy (reduced Pink1/Parkin expression). Mechanistically, miR-4788 directly targets the 3'-UTR of DLG5, downregulating its expression, and restoring the function of DLG5 could alleviate the carcinogenic phenotype caused by miR-4788. CONCLUSIONS: miR-4788 functions as an oncogenic regulator in NSCLC, promoting tumor development by targeting DLG5 and promoting mitochondrial metabolic reprogramming. These findings provide new insights into the miR-4788-DLG5 axis in NSCLC and suggest its potential role in tumor metabolism and immune microenvironment remodeling.