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Long non-coding RNAs and signaling networks in non-small cell lung cancer: mechanistic insights into tumor pathogenesis

Cancer Gene Therapy (2025)Cite this article

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Abstract

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.

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Fig. 1: lncRNA-Mediated Regulation of PI3K/AKT/mTOR, WNT/β-Catenin, and STAT3 Signaling Pathways in non-small cell lung cancer (NSCLC).
Fig. 2: Regulatory Mechanisms of lncRNAs in NSCLC via MEK/ERK, EGFR/IGF-1R, eIF4A3/MUC1/EGFR, and Notch Signaling Pathways.
Fig. 3: LncRNAs regulate miR-451/MDR-1.
Fig. 4: Regulatory roles of lncRNAs in modulating the p53 pathway in NSCLC.
Fig. 5: Dual roles of lncRNAs in regulating the miR-21/PTEN/Akt axis in NSCLC.

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Acknowledgements

The authors are thankful to the Deanship of Graduate Studies and Scientific Research at University of Bisha for supporting this work through the Fast-Track Research Support Program. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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  1. Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, 32897, Egypt

    Hanan Elimam & Khloud Nassar

  2. Department of Pharmacy, Kut University College, Al Kut, Wasit, 52001, Iraq

    Abdullah F. Radwan

  3. Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Cairo, 11829, Egypt

    Abdullah F. Radwan

  4. Program in Biology, Division of Science and Mathematics, New York University Abu Dhabi (NYUAD), Abu Dhabi, United Arab Emirates

    Nadine H. El Said

  5. Biochemistry Department, School of Health and Social Work, University of Hertfordshire Hosted by Global Academic Foundation, New Administrative Capital, 11578, Cairo, Egypt

    Nourhan Elfar

  6. Egyptian Drug Authority (EDA), Ministry of Health and Population, Cairo, 11567, Egypt

    Nourhan Elfar

  7. Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt

    Mai A. Abd-Elmawla

  8. Department of Biochemistry, Faculty of Pharmacy, Ahram Canadian University, Giza, Egypt

    Nora M. Aborehab

  9. Department of Pharmacology, College of Medicine, University of Bisha, Bisha, 61922, Saudi Arabia

    Osama A. Mohammed

  10. Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt

    Ahmed S. Doghish

  11. Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, 11231, Cairo, Egypt

    Ahmed S. Doghish

Authors
  1. Hanan Elimam
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  2. Abdullah F. Radwan
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  3. Nadine H. El Said
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  4. Nourhan Elfar
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  5. Mai A. Abd-Elmawla
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  6. Nora M. Aborehab
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  7. Khloud Nassar
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  8. Osama A. Mohammed
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  9. Ahmed S. Doghish
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Contributions

Conception and design: HE and ASD Collection and/or assembly of the data: AFR, NHES, NE, and K.N. Manuscript writing: NHES, OAM, AFR, MAAE, and HE. All the authors have read and approved the published version of the manuscript.

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Correspondence to Hanan Elimam.

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Elimam, H., Radwan, A.F., El Said, N.H. et al. Long non-coding RNAs and signaling networks in non-small cell lung cancer: mechanistic insights into tumor pathogenesis. Cancer Gene Ther (2025). https://doi.org/10.1038/s41417-025-00950-4

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