Abstract
Globally, gastric cancer (GC) ranks among the deadliest malignancies due to frequent late-stage detection, metastatic dissemination, and resistance to therapies. Emerging evidence highlights N⁶-methyladenosine (m⁶A) modification, orchestrated by methyltransferase-like 3 (METTL3), as a pivotal epigenetic driver of GC pathogenesis. While METTL3 is implicated in promoting tumorigenesis, metastasis, and chemoresistance, a systematic synthesis of its multi-layered regulatory networks and clinical relevance remains elusive. This review comprehensively deciphers METTL3's dual roles as an oncogene and RNA modifier, elucidating its mechanisms in reprogramming GC progression through m⁶A-dependent RNA stability, translation, and non-coding RNA interactions. We reveal novel axes such as HOXA10-TGFβ /Smad-METTL3, METTL3/IGF2BP3-HDGF-glycolysis, and METTL3-YTHDF1- PARP1-driven chemoresistance, underscoring its cross-talk with oncogenic signaling and metabolic reprogramming. Crucially, we pioneer a clinical perspective by evaluating METTL3's diagnostic potential as a biomarker and its therapeutic vulnerability in immunotherapy and NSAID-based strategies. Our analysis identifies METTL3 as a central node in GC's molecular landscape, bridging epigenetic dysregulation with malignant phenotypes and therapy failure. These insights not only redefine METTL3's role in GC but also provide a roadmap for targeting m⁶A machinery in precision oncology.