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Open research questions in MicroRNA in disease regulation

60 unresolved questions extracted from the limitations and future-work sections of 538 MicroRNA in disease regulation papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • Further investigation into the role of the candidate miR-483-3p-METTL3-m6A axis in DOR will be conducted using in vivo models alongside an expanded cohort of clinical samples.

    Overaccumulation of miR-483-3p exerts acute toxic effects on ovarian granulosa cells by impairing cell proliferation, mitochondrial function, and METTL3-mediated m6A modification · 2026 · DOI

  • Hypoxia-driven regulatory mechanisms play a critical role in tumor progression and therapeutic resistance in hepatocellular carcinoma (HCC), yet hypoxia-responsive microRNAs (HRMs) remain incompletely characterized.

    Conserved Hypoxia-Responsive miRNA Programs Define Adaptive and Stress-Limiting Regulatory Axes in Hepatocellular Carcinoma · 2026 · DOI

  • MicroRNA-146a (miR-146a) is a well-recognized negative regulator of inflammatory signaling, primarily through suppression of the NF-κB pathway; however, its broader proteomic impact under inflammatory conditions remains incompletely defined.

    Global Proteomic Analysis Reveals Inflammatory Pathway Modulation Associated with miR-146a in LPS-Stimulated Macrophages · 2026 · DOI

  • miR-100 has been reported as a tumor suppressor in several malignancies; however, its role and downstream regulatory network in lung cancer remain incompletely understood.

    Abstract A065: The Role of miR-100 in lung cancer cell line: Relevance to cancer biology and potential therapy · 2026 · DOI

  • Abstract Objectives Withania somnifera (WS) is known for its adaptogenic benefits; however, its beneficial effects in neurodegenerative diseases have not been fully explored.

    MicroRNA sequencing reveals modulation of neurodegenerative miRNAs by <i>Withania somnifera</i> in human neuroblastoma SK-N-SH cells · 2026 · DOI

  • AimsWhile the muscle-enriched microRNA-378a (miR-378a) has been implicated in cardiac hypertrophy and stress responses, its role in maintaining cardiomyocyte metabolic homeostasis, mitochondrial function, and angiogenic paracrine signaling under physiological and post-injury conditions remains unclear.

    miR-378a Controls Cardiomyocyte Metabolism and Angiogenic Signaling · 2026 · DOI

  • High-throughput sequencing allows for comprehensive small RNA profiling; however, standard commercial library preparation workflows are challenged by issues of low sensitivity and representational bias, limiting reliable profiling, especially in scenarios where samples are scarce.

    Fluorescently guided workflow with rationally engineered 5' ligation adapters for high-sensitivity and low-bias small RNA sequencing · 2026 · DOI

  • Despite the high morbidity and mortality associated with alcohol use disorder (AUD), the molecular mechanisms underlying its sex-specific differences remain poorly understood.

    Urinary extracellular vesicles reveal a sex-specific miRNome profile in alcohol use disorder patients · 2026 · DOI

  • Elu- cidating the molecular mechanisms driving TNBC devel- opment and progression is essential for enhancing disease characterization, supporting further investigation of tissue- based diagnostic biomarkers, and developing targeted thera- pies [32].

    Differential expression of NEAT1 and miR-506-3p in triple-negative breast cancer: potential tissue-based diagnostic biomarkers · 2026 · DOI

  • Discussion These findings indicate that tissue-level miRNA dysregulation in CMTs follows biologically coherent, progression-associated patterns aligned with the roles of human orthologs in breast cancer, whereas no significant circulating signatures were detected in plasma; however, the plasma analyses were limited by a small control group and were underpowered, and these negative findings should not be interpreted as evidence against biological relevance.

    Biphasic tissue expression of cfa-miR-409-3p and cfa-miR-4270 during malignant transformation in canine mammary tumors: an exploratory study · 2026 · DOI

  • Human epidermal growth factor receptor 2 (HER2) remains the most recognized and clinically established molecular biomarker in gastric cancer; however, the regulatory mechanisms underlying its dysregulation are not fully understood.

    Association of Selected miRNAs (hsa-miR-27b, hsa-miR-128-3p, hsa-miR-145-5p, hsa-miR-552-3p) with HER2 Status and Chromosome 17 Centromere Copy Number Increase in Gastric Cancer · 2026 · DOI

  • This study has several limitations that should be considered. First, the findings are based on in vitro experiments using glioblastoma cancer stem cells and therefore may not fully recapitulate the complexity of tumor behavior in vivo. In addition, the drug concentrations used in this study were determined under controlled in vitro conditions and may not directly correspond to clinically achievable exposure levels within the tumor microenvironment. Furthermore, pathway enrichment and network analyses were based on computa- tional predictions and bioinformatic approaches, and thus require further experimental validation. Future studies incor- porating in vivo models and functional assays are needed to confirm the biological relevance of the identified miRNAs, target genes, and associated signaling pathways.

    Temozolomide and ruxolitinib combination modulates miRNA-associated regulatory networks in glioblastoma stem cells · 2026 · DOI

  • Future research should focus on the status of the miR-548as-5p/NF-κB1 axis in the multi-pathway network to provide a basis for more in-depth basic and clinical trans- lational work, thereby offering a more complete strategy for overcoming endocrine drug resistance in breast cancer. The het- erogeneity of endogenous expression in drug-resistant cells was not considered, and future studies are required to confirm the complementary or synergistic effects of the two arms.

    miR-548as-5p promotes breast cancer cell apoptosis and improves tamoxifen resistance by downregulating NF-κB1 · 2026 · DOI

  • Several limitations warrant consideration. Publication bias likely skews the evidence base toward positive results, as studies failing to identify significant hypoxamir effects are inherently less likely to be represented in the literature. Furthermore, this review focused exclusively on solid malignancies across eight distinct cancer types, which may limit the direct applicability of these findings to hematological malignancies [47,48]. Methodologically, the frequent reliance on immortalized cell lines such as THP-1 and RAW264. Seven across the 17-study cohort may not fully capture the physiological complexity of primary human macrophage biology [42,49-51]. Additionally, the use of immunocompromised mouse models in many in vivo validation studies prevents a comprehensive assessment of how the hypoxamir-TAM axis interacts with the adaptive immune system in a fully competent host. Advancing this field requires a transition from the current high-confidence preclinical foundation toward clinical validation and higher-resolution mapping, as summarized in our translational roadmap (Figure 5). Phase I and II trials are necessary to evaluate the safety and efficacy of hypoxamir-targeted therapies, particularly in combination with immune checkpoint inhibitors. At the bench, spatial profiling and multiplex imaging can map the distribution of exosome uptake and macrophage states within human specimens to verify the "metabolic migration" patterns observed in vitro [52-54]. Integrating single-cell multi-omics will allow researchers to capture the transitional states of macrophages as they navigate the tumor-stroma interface. Future work should also explore the synergy between different hypoxamirs, specifically the combined influence of the miR-21 and miR-210 families, which collectively dominate 10 of the studies in the current literature. Prospective cohort studies are required to correlate circulating hypoxamir levels with tumor hypoxia imaging and clinical outcomes, validating their utility as robust liquid biopsy biomarkers for real-time monitoring of the immune microenvironment [55,56]. 2026 Altobi et al. Cureus 18(5): e109827. DOI 10.7759/cureus.109827 8 of 12 FIGURE 5: The translational roadmap Translational roadmap and clinical applications of exosomal hypoxamirsThis visual framework identifies the clinical potential of exosomal hypoxamirs as non-invasive liquid biopsy biomarkers for monitoring tumor hypoxia and TAM infiltration. High expression levels of specific hypoxamir strands (e.g., miR-210, miR-21) correlate with advanced disease stages and poor patient survival, as shown in the prognostic survival curves. The diagram further highlights strategic therapeutic "break points," such as the use of exosome secretion inhibitors (GW4869), antagomirs/LNAs, or small molecule signaling inhibitors to disrupt the pro-tumorigenic axis and restore anti-tumor immunity.

    The Role of Hypoxia-Regulated MicroRNAs (Hypoxamirs) in Tumor-Associated Macrophage Polarization: A Systematic Review · 2026 · DOI

  • Larger cohorts with longitudinal histological assessment are needed to characterize the full spectrum of transcriptomic and histological changes across the progression from diet-induced metabolic perturbation to HCC, as the in vivo HCD model demonstrated only a relatively small sample size that was underpowered to capture comprehensive disease progression phenotypes.

    Integrative transcriptomic analysis reveals miR-26a-5p downregulation and a potential predictive gene signature for the progression of metabolic liver disease · 2026 · DOI

  • Biochemical validation studies are essential to confirm the regulatory relationships between miR-26a-5p and its three identified downstream candidates (EpCAM, DTNA, and KPNA2) in diet-induced liver stress, as protein expression analysis for EpCAM showed only a trend consistent with transcriptomic data rather than definitive confirmation of the proposed miR-26a-5p regulatory network.

    Integrative transcriptomic analysis reveals miR-26a-5p downregulation and a potential predictive gene signature for the progression of metabolic liver disease · 2026 · DOI

  • Single-cell transcriptomics or spatial profiling approaches are necessary to determine the cell-type-specific origin of miR-26a-5p expression and clarify its direct immunomodulatory role in shaping the immune architecture of HCC tumors, as bulk transcriptomic analyses cannot distinguish whether the observed miR-26a-5p and immune-related transcript associations reflect tumor-intrinsic regulation versus differences in tumor cellular composition.

    Integrative transcriptomic analysis reveals miR-26a-5p downregulation and a potential predictive gene signature for the progression of metabolic liver disease · 2026 · DOI

  • While the molecular mechanisms behind POP are not fully understood, previous studies have indicated an association with altered levels of collagen type I and transforming growth factor-beta 1 (TGF-1).

    Deciphering the interplay between NEAT1, miR-139-5p, miR-129-5p, TGF-β1, and collagen type I in pelvic organ prolapse · 2025 · DOI

  • Further investigation into the specific roles of these dysregulated miRNAs is warranted to elucidate their precise involvement in CMT progression and to explore their therapeutic implications.

    Altered miRNA pattern in canine mammary tumors - pilot study · 2024 · DOI

  • Drug-induced gingival overgrowth (DIGO) is recognized as a side effect of nifedipine (NIF); however, the underlying molecular mechanisms remain unknown.

    miR-4651 inhibits cell proliferation of gingival mesenchymal stem cells by inhibiting HMGA2 under nifedipine treatment · 2020 · DOI

  • Absolute quantitation revealed that miRNA abundance varies widely from donor-to-donor, and showed that miR-155-3p abundance is substantially less than miR-155-5p in unstimulated cells.

    Transient up-regulation of miR-155-3p by lipopolysaccharide in primary human monocyte-derived macrophages results in RISC incorporation but does not alter TNF expression · 2019 · DOI

  • In addition to general contribution to the study of pathogenesis mechanisms caused by participation of ATN1, BCL6B, HTT, MAGI1, MLLT3, MN1, THAP11 and TBP genes our analysis allows to propose an adequate experimental animal model for further study of regulation of described genes expression by miR-1322.

    miR-1322 binding sites in mRNAs of genes involved in the development of neurodegenerative and oncological diseases · 2017 · DOI

  • As summarized in this review and in Figure 1, miRNAs represent a novel category of critical regulators in modulating tumor suppressors and oncogenes, or acting as tumor suppressors or oncogenes themselves, in colorectal cancer, participating in the regulation of colorectal cancer initiation, progression, stemness, EMT, metastasis, and chemotherapy response, they also represent promising biomarkers for CRC diagnosis and therapeutic targets for precision oncology. Better understanding of the regulatory roles of miRNAs in colorectal cancer initiation and progression may provide new insights of developing mini-invasive diagnostic tools for CRC screening and personalized therapy. Despite the numerous studies of miRNAs and extensive analyses of their expression, the roles and functions of many individual miRNAs in CRC remain poorly understood. Therefore, the integrated analysis of multiple miRNA targets for a given miRNA, and the integrated bioinformatic analysis of mRNAs, proteins, copy number variants, and mutations from the available public online databases (e.g., The Cancer Genome Atlas database and Oncomine database), are strongly needed. Improving our understanding of the mechanisms of regulatory interactions of mRNAs with the signaling pathways in colorectal cancer stem cells will aid in determining the genes responsible for progression, metastasis, and recurrence and, finally, in developing personalized prevention and therapy. Acknowledgments: This work was supported in part by the grants from the Innovation Team of Science and Technology (grant 13IRTSTHN013 to Wancai Yang) of Henan Province, China, and the Startup Fund from Jining Medical University (to Yongchen Guo and Yonghua Bao). Author Contributions: Wancai Yang conceived and designed the study; Yongchen Guo and Yonghua Bao collected and analyzed the data; and Yonghua Bao and Wancai Yang wrote the paper. Conflicts of Interest: The authors declared no conflict of interest.

    Philosophical Redirection of Educational Research: Human Nature and the Scope of Education. · 1972 · DOI

  • Abstract The role and mechanistic action of MNX1-AS1 in non-small cell lung cancer (NSCLC) remain unclear.

    LncRNA MNX1-AS1 drives the progression of non-small cell lung cancer and serves as a ceRNA to target COMMD8 by sponging miR-218-5p · 2026 · DOI

  • Although preclinical trials have demonstrated positive outcomes of the targeted delivery of miR‑200c into a particular location, a lot of research remains to be conducted regarding delivering the substance efficiently and accurately.

    Advances in miR‑200c regulation of apoptosis, pyroptosis and autophagy in disease (Review) · 2026 · DOI

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60 open questions have been extracted from the limitations and future-work passages of 538 MicroRNA in disease regulation 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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