• lncRNAs as Emerging Regulators of Cellular Stress Pathways in Cancer Progression and Therapy
  • Mahtab Zargarmoradi,1 Taraneh Givi,2 Abolfazl Abdollahi,3 Majid Sadeghizadeh,4,*
    1. Department of Molecular Genetics, Faculty of Biological Sciences, Islamic Azad University Science and Research Branch
    2. Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
    3. Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
    4. Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran


  • Introduction: Cancer cells are constantly challenged by stressful conditions such as oxidative imbalance, hypoxia, nutrient deprivation, and endoplasmic reticulum (ER) stress. These factors activate adaptive responses that not only support tumor survival but also drive drug resistance and metastasis. Long non-coding RNAs (lncRNAs), a class of transcripts longer than 200 nucleotides without protein-coding capacity, have recently emerged as crucial regulators of these cellular stress pathways. Acting as molecular scaffolds, competing endogenous RNAs, or modulators of chromatin and transcriptional activity, lncRNAs integrate stress signals into cellular programs that shape cancer progression and therapy response. This review aims to provide an updated overview of the roles of lncRNAs in stress adaptation and their implications for cancer biology and treatment.
  • Methods: A systematic literature search was performed using PubMed, Web of Science, and Scopus databases for studies published between 2010 and 2025. Keywords included “lncRNA,” “cellular stress,” “oxidative stress,” “ER stress,” “hypoxia,” “autophagy,” and “cancer therapy.” Relevant articles were screened based on title and abstract, and full texts were assessed for inclusion. Both mechanistic and translational studies were considered. Information was synthesized thematically to highlight how lncRNAs regulate specific stress pathways and influence therapeutic outcomes.
  • Results: The collected literature indicates that lncRNAs are deeply involved in multiple stress-related mechanisms. In oxidative stress, lncRNAs modulate redox balance by regulating antioxidant enzymes and reactive oxygen species, thus influencing chemoresistance. Regarding ER stress, lncRNAs interact with the unfolded protein response (UPR), where they can promote pro-survival pathways or shift cells toward apoptosis, highlighting their dual role. Under hypoxia, stress-induced lncRNAs stabilize hypoxia-inducible factors (HIFs), enhancing angiogenesis, metabolic adaptation, and metastatic capacity. In autophagy, lncRNAs either facilitate protective autophagy to support tumor survival or suppress excessive autophagy to prevent cell death, often through ceRNA networks. Importantly, stress-related lncRNAs are strongly linked to therapy resistance, modulating apoptosis, DNA repair, and drug efflux. Emerging approaches suggest that targeting lncRNAs, or using them as carriers in nanoparticle-based drug delivery systems, could overcome resistance and improve therapeutic efficacy.
  • Conclusion: lncRNAs are central regulators of cellular stress responses in cancer, influencing oxidative stress, ER stress, hypoxia, and autophagy. Their ability to shape tumor physiology and modulate drug response positions them as promising biomarkers and therapeutic targets. A deeper understanding of lncRNA-mediated stress regulation, combined with innovative delivery systems, could advance precision medicine and provide new strategies for overcoming therapy resistance.
  • Keywords: lncRNA, Cellular Stress, Cancer, Drug Resistance, Therapy Response