Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality globally, largely attributable to its molecular heterogeneity and resistance to current therapeutic modalities. Dysregulation of key intracellular signaling pathways, including EGFR, PI3K/AKT/mTOR, JAK/STAT, and p53, plays a central role in NSCLC pathogenesis, driving tumor initiation, progression, metastasis, and therapeutic resistance. Increasing evidence highlights long non-coding RNAs (lncRNAs) as critical regulatory molecules within these signaling networks. Aberrant lncRNA expression contributes to oncogenic signaling, modulates the tumor microenvironment, and promotes hallmark cancer traits such as uncontrolled proliferation, evasion of apoptosis, metastasis, and chemoresistance. This review synthesizes contemporary findings on the molecular mechanisms by which lncRNAs influence major oncogenic cascades in NSCLC. Both oncogenic and tumor-suppressive lncRNAs are examined, with an emphasis on their functional interplay with signaling mediators and their contributions to tumor biology. Moreover, the clinical relevance of lncRNAs as diagnostic and prognostic biomarkers is explored, alongside emerging therapeutic strategies designed to target lncRNA-mediated dysregulation. Approaches such as antisense oligonucleotides, RNA interference, and CRISPR/Cas9-based gene modulation offer promising avenues for therapeutic intervention. This review provides a comprehensive framework for understanding the roles of lncRNAs in NSCLC and supports the advancement of lncRNA-targeted precision medicine strategies in lung cancer management.
