MicroRNAs and Their Crosstalk with Oncogenic Pathways in Gastric Cancer

Gastric Cancer (GC) is the fifth most frequently diagnosed malignancy and the third leading cause of cancer-related mortality worldwide. The aggressive nature of GC, coupled with late clinical presentation and limited therapeutic options, underscores the urgent need for a deeper molecular understanding of its pathogenesis. In the past, microRNAs (miRNAs)-evolutionarily conserved, 19-25-nucleotide, non-protein-coding RNAs-have emerged as pivotal post- transcriptional regulators that simultaneously modulate dozens of messenger RNAs through seed-sequence-mediated binding to 3' untranslated regions. In GC, the most intensively studied axes include Notch, Wnt/β-catenin, Hippo, Hedgehog, TGF-β, MAPK, PI3K-AKT-mTOR, and JAK/STAT. Importantly, these pathways do not operate in isolation; instead, they form interconnected networks wherein a single miRNA can create feed-forward or feedback loops that amplify or attenuate oncogenic signaling. Decoding such miRNA-orchestrated crosstalk is not merely an academic exercise; it offers tangible translational opportunities. Restoration of tumor-suppressive miRNAs using synthetic mimics delivered by lipid nanoparticles, or selective silencing of oncomiRs with antagomirs locked by 2'-O-methoxyethyl modifications, has already shown synergistic efficacy with chemotherapy, HER2-targeted agents, and immune checkpoint blockade in preclinical GC models. Moreover, circulating exosomal miRNA signatures that reflect pathway activation states are being vigorously pursued as minimally invasive biomarkers for early detection, molecular subtyping, and real-time monitoring of therapeutic response. In this comprehensive review, we therefore synthesize current mechanistic insights into miRNA- mediated regulation of the aforementioned signaling highways, highlight context-dependent controversies arising from tumor heterogeneity and microbial influence, and outline rational combinatorial strategies that may accelerate the development of next-generation, highly selective, low-toxicity interventions against gastric cancer.