The miR-200 Family in Non-Small-Cell Lung Cancer: Molecular Mechanisms, Clinical Applications, and Therapeutic...

Non-small-cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide, demanding improved biomarkers and therapeutic approaches. This review synthesizes the extensive evidence positioning the miR-200 family as a master regulator of NSCLC progression. We detail the core molecular circuitry centered on the bistable, double-negative feedback loop between miR-200 and the ZEB1/ZEB2 transcription factors, which governs epithelial-mesenchymal transition (EMT). This review connects this central mechanism to critical clinical challenges, including the development of resistance to EGFR-targeted therapies and the regulation of immune evasion through PD-L1 expression and CD8+ T cell infiltration. We evaluate the strong clinical evidence for the miR-200 family's utility as a diagnostic, prognostic, and predictive biomarker. Finally, we explore emerging therapeutic strategies that target this network, including miRNA replacement, epigenetic reactivation, and rational combinations with immunotherapy and targeted agents. We synthesize evidence positioning the miR-200/ZEB feedback circuit as a central regulatory node in NSCLC that links EMT with therapeutic resistance and immune evasion. Beyond summarizing associations, we interpret how this circuitry could inform biomarker development and rational combinations with targeted and immune therapies. Given heterogeneous study designs and non-standardized assays, translational claims remain provisional; we outline immediate priorities for assay harmonization and biomarker-stratified trials.