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Open research questions in Circular RNAs in diseases

26 unresolved questions extracted from the limitations and future-work sections of 99 Circular RNAs in diseases papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • Although the present improvements are consistent with enhanced cell homeostasis after circRNA_013145 silencing, whether these changes are direct consequences of RhoA downregulation or involve addi‑ tional downstream pathways remains to be clarified. Finally, the long‑term efficacy and safety of Ad‑mediated circRNA_013145 silencing remain to be investigated. Third, although the circRNA_013145/miR‑185‑5p/RhoA pathway was experimen‑ tally validated, other potential miRNA targets or RNA‑binding protein interactions of circRNA_013145 were not explored.

    circRNA_013145‑miR‑185‑5p‑RhoA axis: A novel mechanism in the pathophysiology of diabetes‑induced erectile dysfunction · 2026 · DOI

  • Abstract Background Although Esketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is widely used for anesthesia and analgesia and has shown anticancer activity, its effects on lung adenocarcinoma remain unclear.

    Esketamine induces ferroptosis and suppresses immune evasion in lung adenocarcinoma cells via the hsa_circ_0022392/miR-548b-3p/MAP7 axis · 2026 · DOI

  • However, several limitations of the present study should be acknowledged. Conse- quently, the translational relevance of the findings should be interpreted with caution, and future validation in more complex keratinocyte–fibroblast co-culture models and dia- betic wound animal models is warranted.

    Hsa_circ_0006969 aggravates keratinocytes from high-glucose injury by sponging miR-375 to promote USP10 and SCD expression · 2026 · DOI

  • Circular RNAs (circRNAs) are emerging regulators of gene expression and have been implicated in various infectious and inflammatory diseases; however, their role in CCHF remains unknown.

    Circular RNA Expression Profiles in Crimean–Congo Hemorrhagic Fever: Insights into Disease Pathogenesis and Fatal Outcomes · 2026 · DOI

  • First, the functional impact of circEVI5 on other miRNAs or pathways was not explored, leaving room for future multi-omics investigations. Finally, the molecular mechanisms by which GBP2 drives RCC metastasis-such as its role in modulating immune evasion or extracellular matrix remodeling-warrant further study. Future validation in larger multi- subtype cohorts is warranted to assess its utility in rare RCC variants. Future prospective studies with complete WHO/ISUP grading data are warranted to validate our findings.

    Circular RNA circEVI5 functions as a miR-433 sponge to promote renal cell carcinoma progression via GBP2-mediated oncogenic signaling · 2026 · DOI

  • Abstract Juvenile myoclonic epilepsy (JME) is one of the most common idiopathic generalized epilepsy syndromes, yet its molecular pathogenesis remains incompletely understood.

    Dysregulated circRNA Expression in Juvenile Myoclonic Epilepsy · 2026 · DOI

  • CircRNAs represent a paradigm of multidimensional, highly integrated regulation in the molecular pathology of HF. They not only participate in myocardial remodeling by regulating key processes such as myocardial hypertrophy, cardiomyocyte apoptosis, myocardial fibrosis, inflammatory responses, and calcium signaling pathways, but also form complex signaling networks with miRNAs, RBPs, exosomes, and their own encoded small peptides, demonstrating their potential as upstream integration hubs in the HF pathology process. This bidirectional regulatory characteristic - the existence of both pro-pathogenic and protective circRNAs - provides the possibility of precise intervention, making selective molecular intervention targeting specific circRNAs or their downstream axes the theoretical basis for “directional correction” of myocardial pathological processes. Simultaneously, the stability and detectability of circRNAs in blood and EVs make them potential biomarkers for the diagnosis, risk stratification, and dynamic monitoring of HF and myocardial infarction, potentially driving the development of personalized medicine strategies. Page 16 of 20 Wang et al. Vessel Plus. 2026;10:21 Despite this commitment, the process of translating basic research into clinical applications is fraught with numerous challenges, including complex expression patterns, differences between animal models and human physiology, as well as significant obstacles in treatment delivery and safety. Future research will need to combine large mammalian models, human tissue samples, and exosome or nucleic acid modification technologies to enhance the feasibility and safety of circRNA-related therapeutic strategies. The key point is that current literature primarily relies on the pressure overload model, which predominantly induces concentric hypertrophy. The specific role of circRNA in diastolic hypertrophy caused by volume overload remains largely unexplored. Since pressure overload and volume overload activate distinctly different mechanical signal transduction pathways, it is imperative to conduct research using the volume overload model in the future to comprehensively characterize circRNA profiles under various biomechanical stress conditions. Moreover, given the well-recognized sex differences in HF epidemiology, remodeling patterns, and clinical outcomes, future investigations should incorporate sex as a biological variable to determine whether circRNA expression profiles and regulatory networks exhibit sex-specific characteristics[91]. Speculatively, by modulating calcium signaling and excitation-contraction coupling, circRNAs may serve as potential therapeutic targets for arrhythmias and contractile dysfunction, highlighting a novel translational avenue beyond conventional structural remodeling interventions. Furthermore, recent studies have implicated circRNAs in anthracycline-induced cardiotoxicity, in which they modulate cardiomyocyte apoptosis, oxidative stress, and mitochondrial dysfunction in doxorubicin-treated models, thereby expanding their relevance to chemotherapy-related cardiac injury[92]. In conclusion, circRNAs are not merely tools for dissecting disease mechanisms; they are foundational to a forward-thinking vision for cardiovascular medicine, representing a key translational breakthrough for diagnosing and treating HF. DECLARATIONS Authors’ contributions Made substantial contributions to the conception, performed literature search, and wrote the initial draft of the manuscript: Wang X Assisted in design of the study, literature collection, discussions, and coordination of the manuscript: Sun W Provided critical guidance, reviewed and revised the manuscript, and approved the final version for submission: Gong W, Nie S All authors read and approved the final manuscript.

    Circular RNAs: key orchestrators of pathological remodeling in heart failure · 2026 · DOI

  • The intracellular trafficking of ICAM-1 following circAFF3 depletion is proposed to represent trafficking intermediates, but the complete mechanism and kinetics of this trafficking process require further characterization.

    CircAFF3 modulation of p53–ID2 signaling in the retinal pigment epithelium links inflammation with cell death in dry age-related macular degeneration · 2026 · DOI

  • While findings in ARPE-19 cells are suggested to be relevant in human dry AMD based on gene expression patterns, direct validation in primary human RPE cells or in vivo human models would strengthen the translational relevance.

    CircAFF3 modulation of p53–ID2 signaling in the retinal pigment epithelium links inflammation with cell death in dry age-related macular degeneration · 2026 · DOI

  • Over the past decade, ICIs have been developed and approved for clinical use in multiple cancer types at an unprecedented rate. Despite tremendous progress, ICIs have not completely solved the problem of cancer treatment. Besides discovering biomarkers to predict the efficacy and safety of ICIs, more immune checkpoint molecules may need to be identified in the next decade to provide more options for immunotherapy and bring treatment opportunities to more patients, which depends on our insights into the mechanisms of immune checkpoint regulation. This review sum- marizes the status quo of frequent immune checkpoints and ICIs commonly applied in cancer, such as anti-PD-1/PD-L1, anti-CTLA-4, anti-LAG-3, anti-TIM-3, and other immune checkpoints targeted mAbs. The regulatory mechanisms of immune checkpoints are complex and unclear, which stem from its complicated and diverse influencing factors, involving ncRNAs, proteins, and other elements. As a class of abundant component of the human transcriptome involved in cancer hallmarks, ncRNAs are closely associated with the expression regulation of the structure’s stability, circRNAs present significantly greater advantages and potential as diagnostic and prognostic biomarkers for cancer management than other types of ncRNAs. Also, circRNAs have been confirmed to involve in various cancer hallmarks including prolifera- tion, cell death, inflammation, angiogenesis, invasion and metastasis interacting with proteins, through functioning as miRNA sponge, encoding proteins, or other unclarified mechanisms. immune checkpoints.

    Mechanisms of immune checkpoint inhibitors: insights into the regulation of circular RNAS involved in cancer hallmarks · 2024 · DOI

  • Circular RNAs (circRNAs) are a distinct class of stable, non-coding transcripts increasingly recognized as key regulators of cancer biology, yet their role in brain-tropic metastasis remains poorly defined.

    Circular RNA dynamics in breast-to-brain metastatic cascade · 2026 · DOI

  • Previous studies have shown that circRNAs are capable of regulating muscle development; however, relatively few reports have addressed their association with buffalo muscle development.

    CircCOPS8 Inhibits the Proliferation of Buffalo Myoblasts by Binding to IGF2BP3 and Promoting ATR Gene Expression · 2026 · DOI

  • Finally, the downstream pathways through which cFKBP8 affects α-synuclein aggregation remain unknown and require fur- ther investigation. However, several limitations of this study need to be acknowledged.

    circFKBP8(5S,6)-encoded protein modulates α-synuclein expression in SH-SY5Y cells · 2026 · DOI

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26 open questions have been extracted from the limitations and future-work passages of 99 Circular RNAs in diseases papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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