NcRNAs in the Wnt/β-catenin signaling pathway: from multidimensional mechanisms to diagnostic and therapeutic translation in non-small-cell lung cancer

<sec><p indent="0mm">Lung cancer (LC) is the leading cause of cancer-related deaths worldwide, with non-small-cell lung cancer (NSCLC) constituting the majority of cases. Effective treatment is hampered by an incomplete understanding of molecular mechanisms, insufficient early-detection tools, and widespread drug resistance. The Wnt/β-catenin signaling pathway, central to lung tissue homeostasis, is frequently dysregulated in NSCLC and drives malignant transformation and progression. Accumulating evidence indicates that non-coding RNAs (ncRNAs)—including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs)—are critical modulators of this pathway. However, the multilayered regulatory networks they form, as well as strategies for their clinical translation, remain incompletely defined. </sec><sec> This review synthesizes current knowledge on how diverse ncRNAs target the Wnt/β-catenin pathway in NSCLC, addressing their impacts on ligand secretion, receptor activation, intracellular signal transduction, and negative regulators. It outlines a multidimensional regulatory landscape in which ncRNAs collaboratively promote or suppress NSCLC by modulating Wnt/β-catenin signaling and evaluates their potential as biomarkers and therapeutic targets. </sec><sec> Mechanistically, ncRNAs operate at transcriptional, post-transcriptional, translational, and epigenetic levels to influence cancer stem cell maintenance, epithelial–mesenchymal transition, angiogenesis, proliferation, metastasis, and therapy resistance. miRNAs commonly bind the 3ʹ untranslated regions of mRNAs encoding pathway components–such as secreted frizzled-related proteins, Dickkopf family members, GSK-3β, AXIN1, and β-catenin–thereby fine-tuning their expression and directly influencing malignant behaviors. Many lncRNAs act as competing endogenous RNAs (ceRNAs), sequestering specific miRNAs to relieve repression of target transcripts and activate Wnt signaling; others function as signals, scaffolds, decoys, or guides to regulate transcription factors and pathway components. Owing to their covalently closed structure, circRNAs are stable and primarily function as miRNA sponges; a subset also encodes functional peptides that influence phosphorylation, ubiquitination, or stability of Wnt/β-catenin components. </sec><sec> Therapeutically, ncRNAs function as pivotal regulatory nodes and represent promising targets for intervention. They are centrally involved in mechanisms of drug resistance, indicating that targeting the ncRNA–Wnt/β-catenin axis could synergize with existing treatments. Advances in RNA delivery platforms and RNA-based therapeutics offer promising routes to reverse resistance and remodel the tumor microenvironment. Additionally, natural compounds with multi-target activity and small molecules that modulate specific ncRNAs provide complementary strategies to accelerate drug discovery and personalize therapy. </sec><sec> In diagnostics, Wnt/β-catenin-related ncRNAs show considerable promise as clinical biomarkers throughout the management of NSCLC, including early detection, molecular subtyping, metastasis surveillance, recurrence monitoring, prognosis, and resistance assessment. High-throughput sequencing and comprehensive expression profiling have identified candidate ncRNA biomarkers showing promise for high sensitivity and specificity in preliminary studies, which require rigorous clinical validation. </sec><sec> Integrated multi-omics and functional studies are needed to decode ncRNA regulatory networks in NSCLC systema- tically. Establishing a translational pipeline from “mechanistic discovery → targeted therapeutic development → biomarker validation” will be critical to moving ncRNA findings from bench to bedside and ultimately improving the diagnosis and treatment of NSCLC. </sec>