Multiomics Reveals NDRG1-Driven Oral Squamous Cell Carcinoma Progression: Competitive Endogenous RNAs Regulation and Proangiogenic Microenvironment Remodelling

Oral squamous cell carcinoma (OSCC) is characterized by high aggressiveness. This study aims to elucidate the role of NDRG1 in the evolutionary heterogeneity and spatial microenvironmental remodelling of OSCC. By integrating bulk transcriptomics, single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics (ST), complemented by in vivo and in vitro functional assays, we systematically explored the regulatory logic of the MSTRG.47889/miR-1299/NDRG1 axis. The MSTRG.47889/miR-1299/NDRG1 ceRNA regulatory axis was identified and validated, demonstrating its significant role in promoting OSCC proliferation and invasion while impairing cellular adhesion. Single-cell analysis revealed a significant expansion of the NDRG1-high subpopulation in tumour tissues, which drives cellular evolution along a pseudotime trajectory toward a partial epithelial-mesenchymal transition (p-EMT) and a high glycolytic state. Spatial transcriptomics analysis revealed that NDRG1 is highly expressed within 'hypoxia-metabolic' niches. Our integrative analysis suggests that these regions may coordinate with endothelial cells, highlighting a potential role for the ANGPTL4-CDH5 signalling axis in promoting a proangiogenic microenvironment. These findings provide preliminary insights into how NDRG1 serves as a pivotal regulator driving p-EMT and coordinating niche remodelling. NDRG1 serves as a pivotal regulator driving p-EMT and proangiogenic niche remodelling, representing a potential novel target for the diagnosis and treatment of OSCC.