METTL3-driven m⁶A modifications in esophageal squamous cell Carcinoma: Emerging mechanisms, biomarker potential, and...

Esophageal squamous cell carcinoma (ESCC) remains a highly aggressive malignancy with limited diagnostic and therapeutic advancements, underscoring the urgent need for novel biomarkers and targeted therapies. Methyltransferase-like 3 (METTL3), a pivotal regulator of N⁶-methyladenosine (m⁶A) RNA modification, has emerged as a critical player in cancer pathogenesis. This review synthesizes current evidence to elucidate METTL3's multifaceted roles in ESCC progression, metastasis, and therapeutic resistance. Mechanistically, METTL3 promotes tumorigenesis by orchestrating m⁶A-dependent regulation of oncogenic pathways, including EGR1/Snail, Notch, and c-Myc signaling, while suppressing tumor suppressors like APC. Clinically, METTL3 overexpression correlates with advanced tumor stage, lymph node metastasis, and poor prognosis, highlighting its diagnostic and prognostic utility. Furthermore, METTL3 enhances radioresistance via DNA repair modulation and drives metabolic reprogramming through targets such as GLUT1 and GLS2. Emerging therapeutic strategies targeting METTL3, including small-molecule inhibitors [e.g., Elvitegravir] and RNA-based interventions, demonstrate preclinical efficacy in suppressing ESCC proliferation and metastasis. This review also identifies critical knowledge gaps, such as the interplay between METTL3 and tumor microenvironment dynamics, and advocates for multicenter studies to validate its clinical applicability. Collectively, our findings position METTL3 as a promising biomarker and a tractable therapeutic target, offering actionable insights to advance ESCC management.