This narrative review synthesizes relevant cellular and molecular studies to delineate the potential pathophysiological mechanisms

The gap

Evidence profile

Sourced from the future work of the source papers, classified as general, spanning 2 journals. Those papers have been cited 2 times in total.

Supporting evidence — 3 representative gaps

• Emerging functions of m6A-modified circRNAs and their targeting strategies in lung cancer (2026) · Frontiers in Cell and Developmental Biology · doi

  including tumor growth, metastasis, m6A dynamically modulates circRNA biogenesis, stability, and translation, while circRNAs reciprocally regulate the m6A machinery and act as scaffolds to fine-tune gene expression (Qin et al., 2021). Functionally, this interplay governs key cancer hallmarks, ferroptosis, stemness, therapy resistance, metabolic reprogramming, and immune microenvironment remodeling (Du et al., 2022). Clinically, m6A-modified circRNAs hold great promise as diagnostic biomarkers due to their stability, tissue specificity, and reflection of disease states (Xu et al., 2024). Furthermore, targeting the m6A–circRNA axis offers innovative therapeutic avenues, either by modulating m6A regulators or by manipulating circRNAs directly through RNA-based interventions (Androsavich, 2024). Overall, elucidating the m6A–circRNA network not only enhances our understanding of lung cancer pathogenesis but also provides a foundation for precision diagnostics and tailored therapeutic strategies. Firstly, the regulatory modes by which m6A affects circRNAs are highly diverse. m6A can influence circRNA biogenesis, stability, subcellular localization, and translational potential, while different m6A writers, erasers, and readers may exert distinct or even opposing effects depending on the cell type or physiological and pathological context. For instance, m6A writers may promote back- splicing and circRNA generation in some cases, whereas in others they may suppress circRNA expression. Similarly, m6A readers can either stabilize circRNAs or facilitate their degradation, exhibiting bidirectional regulatory features. Such multilayered regulation suggests that the m6A–circRNA network is not a simple linear pathway, but rather a highly dynamic regulatory system. Secondly, the functional outcomes of m6A-mediated circRNA regulation vary markedly across different cancers and even among subtypes of the same cancer, which is closely linked to tumor heterogeneity. The same m6A–circRNA axis may act as an oncogenic driver in one tumor type while functioning as a tumor suppressor in another. This divergence may be attributed to differences in genetic mutation backgrounds, microenvironmental contexts, expression profiles of m6A regulators, and downstream target networks. Therefore, future studies should integrate tumor subtypes, staging, and treatment status for refined analysis to elucidate the specific roles of m6A–circRNA interactions under distinct pathological conditions. Thirdly, m6A modification can promote the translation of circRNA-encoded peptides or microproteins, providing a new dimension for circRNA function. Increasing evidence indicates that some circRNAs possess translational potential, and their encoded peptides play key roles in tumor cell proliferation, apoptosis, migration, and drug resistance. As a translational initiation mark, m6A may facilitate peptide production by recruiting translation initiation complexes or altering circRNA structures to enhance ribosome recognition. This field is still in its infancy, and more systematic studies are needed to validate the biological significance and clinical relevance of m6A-dependent circRNA translation. Finally, beyond m6A, it remains an important unresolved question whether other RNA modifications, such as m5C and ac4C, similarly regulate circRNA expression and function. Existing studies have shown that m5C and ac4C modifications significantly influence mRNA stability, translation efficiency, and nuclear export; however, their roles in circRNA biology are relatively underexplored. Future multi-omics analyses may uncover a more comprehensive “circRNA epitranscriptome” and elucidate how different modifications interact to shape tumor biology. Overall, the m6A–circRNA interaction network offers a novel perspective for cancer research, but its complexity suggests that higher-throughput and more refined research strategies—combining single-cell sequencing, structural biology, and clinical validation—are required to translate discoveries into precise diagnostic and therapeutic approaches.

  generalfuture work
  Keywords: circrna tumor circrnas translation stability expression cancer therapeutic network regulatory translational different cell roles modifications
• Impact of Epigenetic Modifications in Airway Diseases. Role of Inflammation, Environmental Factors and Aging (2026) · Lung · doi

  Recent advances have clarified the role of epigenetic mechanisms in inflammatory airway diseases, showing that they mediate gene–environment interactions and influence Page 15 of 21 51 inflammation, tissue remodeling, and cellular transforma- tion. This conceptual framework describes how epigenetic mechanisms, including DNA methylation, histone modifi- cations, and ncRNAs regulate key molecular and cellular processes involved in chronic respiratory diseases such as asthma and COPD. Dysregulation of these processes con- tributes to chronic inflammation, immune imbalance, epi- thelial dysfunction, and disease progression. The dynamic and reversible nature of epigenetic mechanisms also pro- vides opportunities for clinical applications, particularly through the development of non-invasive biomarkers detectable in airway samples, blood, or exhaled breath, useful for diagnosis, prognosis, and treatment monitoring. Today epigenetic therapies are increasingly being explored for lung diseases. Additionally, the use of miRNA mimics and antagomirs, which modulate post-transcriptional gene expression, holds potential for targeted treatments in condi- tions such as inflammation and fibrosis. More recently, have emerged as promising approaches to precisely reprogram disease-associated epigenetic marks, potentially offering improved specificity and reduced off-target effects com- pared with earlier techniques [142]. Looking ahead, key research directions aim to translate epigenetic knowledge into clinical practice. A major focus is the integration of multi-omics approaches combining epig- enomics, transcriptomics, proteomics, and metabolomics to better characterize gene–environment interaction networks driving disease, enabling the identification of novel bio- markers and therapeutic targets [143]. Longitudinal cohort studies are also essential to clarify causal links between epigenetic changes and disease onset or progression, sup- porting the development of early diagnostic markers and effective interventions. Overall, personalized epigenetic medicine may improve the management of chronic respira- tory diseases by tailoring therapies to each patient’s genetic and environmental profile. Acknowledgements The authors would like to thank the National Research Council (CNR) for the institutional support. Author Contributions All authors contributed to the study conception and design. The first draft of the manuscript was written by CDA and CDS. All authors (AMM, RPG, MG and FLMR, MP) commented the first versions of the manuscript. MP revised the final version of the manuscript. All authors read and approved the final version of the re- view. Funding Open access funding provided by Consiglio Nazionale Delle Ricerche (CNR) within the CRUI-CARE Agreement. The authors de- clare that no funds, grants, or other support were received during the preparation of this manuscript. Data Availability No datasets were generated or analysed during the current study. 1 3Lung (2026) 204:51  51 Page 16 of 21

  generalfuture work
  Keywords: epigenetic authors diseases disease manuscript mechanisms gene inflammation chronic airway environment page cellular processes progression
• Obstructive sleep apnea and lung cancer: molecular underpinnings and clinical translational prospects (2026) · Frontiers in Cell and Developmental Biology · cited 2× · doi

  6.1 Conclusions This narrative review synthesizes relevant cellular and molecular studies to delineate the potential pathophysiological mechanisms underlying the bidirectional crosstalk between OSA and lung cancer (Figure 2). In recent years, the TME has drawn much attention as a potential target for cancer immunotherapy (Schulz et al., 2019; Keremitçi et al., 2025). Mechanistically speaking, OSA-associated hypoxia modulates the TME via multiple synergistic pathways, with oxidative stress and chronic inflammation induced by CIH acting as core regulatory hubs. Specifically, on the one hand, CIH promotes induce exosome secretion by tumor cells; these exosomes M2 polarization of tumor-associated macrophages via their carried miR-106a-5p (Ren et al., 2024) and simultaneously upregulate PD-L1 expression on macrophage surfaces (Liu Y. immunosuppressive et al., 2022), ultimately establishing an microenvironment that impairs anti-tumor immunity. On the other hand, CIH activates the HIF-1α/ATAD2 and HIF-1α/ ESM1 pathways to upregulate the expression of cancer stem cell markers such as CD133 and CD44, enhancing the invasive and metastatic capabilities of lung cancer cells (Gu et al., 2021; Hao et al., 2022). Notably, SF also participates in regulating this process via CD8+ T cells (Akbarpour et al., 2017). Meanwhile, sympathetic hyperactivity accelerates tumor progression and increases metastasis incidence through the βARs signaling pathway, while SF further promotes tumor growth and angiogenesis via the same pathway (Powell et al., 2013; Cui et al., 2021; Sun et al., 2024; Wheeler et al., 2021; Lourenço et al., 2022). Collectively, these findings indicate that CIH, SF, and sympathetic hyperactivity synergistically drive TME remodeling, initiation and progression. lung cancer facilitating thereby A vicious cycle defines the bidirectional interplay between OSA and lung cancer: airway obstruction and inflammatory responses caused by lung cancer itself, along with tumor hypoxia and sleep disturbances induced by anti-tumor therapies (chemotherapy, radiotherapy, targeted therapy), may trigger or worsen OSA; the conversely, OSA aforementioned pathways. These regulatory pathways do not operate in isolation but are interconnected through oxidative stress and inflammatory factors (e.g., TNF-α, IL-6, IL-8) as intermediate mediators, ultimately forming a pro-tumorigenic network of “CIH/SF/sympathetic hyperactivity - oxidative stress/ chronic inflammation - immunosuppression/immune escape.” tumor progression via accelerates clinical management of both Nevertheless, several gaps remain in current research: first, a few studies have not found a significant association between OSA and lung cancer incidence or

  generalfuture work
  Keywords: cancer tumor lung pathways oxidative stress cells sympathetic hyperactivity progression potential bidirectional associated hypoxia chronic

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