METTL3-mediated m 6A modification facilitates Nectin-4-induced VNN1 upregulation and promotion of ESCC progression.

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with poor prognosis and limited therapeutic options. N6-methyladenosine (m ⁶A) RNA modification plays a role in tumorigenesis, but its contributions to ESCC and the regulation of cell adhesion molecules such as Nectin-4 are not fully elucidated. In this study, we investigate the role and the regulatory mechanisms of Nectin-4 in ESCC, particularly regarding the influence of m ⁶A modification and its downstream metabolic effects. Our study demonstrates that methyltransferase-like protein 3 (METTL3) enhances Nectin-4 mRNA stability and expression through m ⁶A methylation in ESCC, as validated by actinomycin D assay, MeRIP-qPCR, and dual-luciferase reporter assay. Both METTL3 and Nectin-4 are highly expressed in ESCC tissues and promote malignant phenotypes such as proliferation, migration, and invasion. Further analysis identifies pantothenate esterase 1 (VNN1) as a downstream target of Nectin-4, mediating the oncogenic effects of the METTL3/Nectin-4 axis and promoting the biosynthesis of pantothenic acid and coenzyme A, thus driving ESCC progression. By integrating transcriptomic data, this study elucidates a key pathogenic mechanism in which the METTL3/Nectin-4/VNN1 axis regulates metabolic reprogramming to promote ESCC development. These findings provide new insights into the molecular pathology of ESCC and offer potential biomarkers and therapeutic targets for early screening, prognosis, and precision treatment for ESSC.