Open research questions in MicroRNA in disease regulation

What the literature leaves open

• This review systematically elucidates recent advances in miRNA research in acute and chronic heart failure (AHF/CHF). It covers the posttranscriptional regulatory roles of miRNAs in core pathophysiological processes such as myocardial apoptosis, inflammation, hypertrophy, and fibrosis, as well as their stagespecific, cell typespecific, and contextdependent dualfunction mechanisms. The article focuses on the potential of circulating miRNAs as diagnostic and prognostic biomarkers for heart failure, therapeutic strategies involving miRNA mimics and inhibitors, and the technical challenges in clinical translation. From a precision medicine perspective, it explores the integrated application of miRNAs in the refined stratification of heart failure subtypes, early warning, and targeted therapies aimed at delaying disease progression and preserving cardiac function. Despite significant progress achieved in basic and clinical research, translating miRNA-based findings into clinical practice remains hindered by unresolved challenges, including incomplete mapping of miRNA regulatory networks, insufficient diagnostic specificity of single miRNA markers, and technical barriers in targeted delivery systems, immunogenicity control, and off-target effect mitigation. To address these gaps and promote the sustainable development of the field, future studies should focus on the following key aspects based on the miRNA classification framework of pathological mechanisms and transformation potential, clarifying the stage-specific and cell-type-specific regulatory roles of miRNAs in HF, improving the accuracy and specificity of miRNA-based biomarkers through multi-omics integration, optimizing myocardial-specific targeted delivery systems to reduce immunogenicity and off-target effects, and strengthening large-scale preclinical verification and clinical trials to ensure the safety and efficacy of miRNA therapies. Meanwhile, it is necessary to learn lessons from past clinical failures to avoid repeated risks. In summary, miRNAs are key regulators of AHF and CHF, and their in-depth study is of great significance for clarifying the pathological essence of HF and promoting the development of precise diagnosis and treatment strategies. With the continuous improvement of research technologies and the breakthrough of key technical bottlenecks, it is expected that miRNAs will revolutionize the diagnosis, treatment, and prognosis evaluation of HF, promote the realization of personalized HF management, and ultimately improve the clinical outcomes of patients with HF. DECLARATIONS

  The role of microRNAs in acute and chronic heart failure: a key regulator and therapeutic target · 2026 · DOI

• The molecular mechanisms underlying LNM in ESCC are not well understood. Effective biomarkers for early diagnosis and therapeutic targets are lacking.

  EV-derived miR-1246 promotes lymph node metastasis in esophageal squamous cell carcinoma through targeting the PPP2CB/NF-κB axis · 2026 · DOI

• Lack of detailed mechanistic insight into how the MIAT/miR-150 axis regulates heart failure and cardiomyocyte apoptosis. Deficit of definitive studies using mouse models to establish the functional relationship between MIAT, miR-150, and HOXA4. Limited understanding of the role of HOXA4 in cardiomyocyte apoptosis and its regulation by the MIAT/miR-150 axis.

  Homeobox a4 is proapoptotic in the AC16 human cardiomyocyte cell line and a key effector of the MIAT/miR-150 axis in murine myocardial infarction · 2026 · DOI

• Further studies are needed to evaluate the sex-dependent effects of the miRNA cluster inhibition, - Investigation of the role of non-coding RNAs from the Dlk1-Dio3 locus in the development of diabetes and other metabolic alterations in humans

  Combinatorial targeting of the miR-379/miR-410 cluster normalizes glucose and lipid homeostasis in male models of diabetes and obesity · 2026 · DOI

• The role of microRNAs from the miR-379/miR-410 cluster in mature organs, particularly in the context of glucose and lipid homeostasis, is not well understood. The potential of hepatocyte-specific decoy therapy as a therapeutic approach for diabetes and obesity has not been explored.

  Combinatorial targeting of the miR-379/miR-410 cluster normalizes glucose and lipid homeostasis in male models of diabetes and obesity · 2026 · DOI

• exploring biomarkers in other tissues, such as urine and saliva, offers promising avenues for future research, - cohort studies may serve as an important approach to establishing causal relationships, - future research leveraging artificial intelligence and machine learning is expected to further enhance the predictive power of multi-omics technologies

  Multi-omics approaches for biomarker discovery and precision diagnosis of prediabetes · 2025 · DOI

• Limitations of traditional diagnostic methods in early detection and personalized interventions. Lack of clear concentration thresholds for diagnosing prediabetes. Need for cohort studies to establish causal relationships and validate biomarkers.

  Multi-omics approaches for biomarker discovery and precision diagnosis of prediabetes · 2025 · DOI

• Abstract Background MicroRNA-2110 has been implicated in cancer, but its expression and function in gastric cancer (GC) remain understudied.

  MicroRNA-2110 acts as a tumor suppressor in gastric cancer via direct targeting of IGF1R · 2026 · DOI

• Regular physical activity is a powerful non-pharmacological strategy for preventing and managing cardiovascular diseases (CVDs), including heart failure, by promoting cardioprotective adaptations through molecular mechanisms that remain incompletely elucidated.

  MicroRNA, MicroRNA-lncRNA and MicroRNA-Circular RNA axes, and exosomal MicroRNAs: driving exercise-induced cardioprotection in heart failure · 2026 · DOI

• However, clinical translation remains limited by the lack of standardized isolation and quantification protocols, tumor and patient heterogeneity, and the predominantly associative nature of current evidence.

  MicroRNAs in Cutaneous Melanoma: Biological Roles, Clinical Utility, and Future Directions · 2026 · DOI

• However, the intricate molecular mechanisms underlying TAM-induced chemoresistance remain incompletely understood.

  Exo-miR-1911-5p regulates ferroptosis to promote macrophages M2 polarization-mediated gastric cancer cisplatin resistance via MYB/AKR1B10/ACC · 2025 · DOI

• Future research should focus on overcoming these barriers, ultimately paving the way for the widespread adoption of personalized miRNA-based nanomedicine in cancer therapy.

  Integration of MicroRNAs with nanomedicine: tumor targeting and therapeutic approaches · 2025 · DOI

• However, the exact pathogenesis of PD remains unclear, with ferroptosis emerging as one of the key factors driven by iron accumulation and lipid peroxidation.

  Glial cells improve Parkinson’s disease by modulating neuronal function and regulating neuronal ferroptosis · 2025 · DOI

• CAR-T cell and immune checkpoint blockade immunotherapies are in clinical trials for their ability to enhance durable anti-AML immune responses, but have yielded mixed results.

  MicroRNA regulation of messenger RNA vaccine responses in a mouse model of acute myeloid leukemia 3050 · 2025 · DOI

• Future research should focus on experimentally confirming their regulatory roles through functional assays, conducting transcriptomic comparisons across different species, and performing target validation studies.

  Fish MicroRNA Responses to Thermal Stress: Insights and Implications for Aquaculture and Conservation Amid Global Warming · 2025 · DOI

• However, the interaction between lactylation and miRNA networks remains largely underexplored.

  Lactylation-mediated miRNA regulation in cancer therapy resistance · 2025 · DOI

• Background microRNAs (miRNAs) are key post-transcriptional regulators of gene expression in animals, yet their origins and early functions remain elusive.

  Identification and Functional Characterization of microRNAs in Ichthyosporea · 2025 · DOI

• However, the cellular process of various miRNAs in CMECs in cardiovascular diseases has not been fully elucidated.

  Role and mechanism of miRNA in cardiac microvascular endothelial cells in cardiovascular diseases · 2024 · DOI

• Aims MiR-181c-5p overexpression associates with heart failure (HF) and cardiac damage, but the underlying pathophysiology remains unclear.

  Divergent cardiac and renal effects of miR-181c-5p inhibition in a rodent heart failure model · 2024 · DOI

• Aging is a consequence of complex molecular changes, but whether a single microRNA (miRNA) can drive aging remains unclear.

  miR-29 is an important driver of aging-related phenotypes · 2024 · DOI

• Previous studies have demonstrated the involvement of microRNA-143-3p (miR-143-3p) in the process of fear memory and pathogenesis of ischemia; however, the relationship between miR-143-3p and depression remains poorly understood.

  miR-143-3p modulates depressive-like behaviors via Lasp1 in the mouse ventral hippocampus · 2024 · DOI

• BACKGROUND AND OBJECTIVES: Post-ischemic stroke (IS) outcomes vary widely among individuals, independently of clinical factors.

  Circulating miRNAs Associated With 3-Month Outcome in Patients With Acute Ischemic Stroke · 2024 · DOI

• While several microRNAs (miRNAs) and their target genes are implicated in the pathophysiology of IS, their role in functional outcomes remains unclear.

  Circulating miRNAs Associated With 3-Month Outcome in Patients With Acute Ischemic Stroke · 2024 · DOI

• Additionally, many studies have shown the importance of post-transcriptional regulation of signaling and network components mediated by microRNAs (miRNAs); however, how miRNAs are transcriptionally regulated is poorly understood.

  Transcription of microRNAs is regulated by developmental signaling pathways and transcription factors · 2024 · DOI

• Although previous reviews have indicated the significance of microRNAs (miRNAs) in bone metabolism, their roles in orchestrating maxillofacial bone modeling and remodeling remain unclear.

  MicroRNAs in maxillofacial bone modeling and remodeling: implications for malocclusion development and orthodontic treatment · 2024 · DOI

Most-cited papers in MicroRNA in disease regulation

• The functions of animal microRNAs · Nature · 2004 · 9,024 citations
• MicroRNA expression profiles classify human cancers · Nature · 2005 · 7,882 citations
• Identification of Novel Genes Coding for Small Expressed RNAs · Science · 2001 · 3,900 citations
• Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs · Nature · 2005 · 3,897 citations
• The nuclear RNase III Drosha initiates microRNA processing · Nature · 2003 · 3,823 citations
• Mammalian microRNAs predominantly act to decrease target mRNA levels · Nature · 2010 · 3,360 citations
• Silencing of microRNAs in vivo with ‘antagomirs’ · Nature · 2005 · 3,353 citations
• The impact of microRNAs on protein output · Nature · 2008 · 3,049 citations
• A microRNA polycistron as a potential human oncogene · Nature · 2005 · 2,921 citations
• Widespread changes in protein synthesis induced by microRNAs · Nature · 2008 · 2,891 citations

Most recent work

• MicroRNA, MicroRNA-lncRNA and MicroRNA-Circular RNA axes, and exosomal MicroRNAs: driving exercise-induced cardioprotection in heart failure · Frontiers in Cell and Developmental Biology · 2026
• One-pot room-temperature visualization platform combining strand displacement amplification and rolling circle amplification for the sensitive detection of microRNAs with a smartphone · Sensors and Actuators B: Chemical · 2026
• Host-directed microRNA-based intervention against intracellular Staphylococcus aureus: high-throughput screening identifies miR-4430, miR-147a, and miR-1249-5p as multifunctional antimicrobial candidates · Frontiers in Cellular and Infection Microbiology · 2026
• Animal virus-host interactions mediated by non-coding RNAs · Frontiers in Cellular and Infection Microbiology · 2026
• Engineered Akkermansia muciniphila extracellular vesicles for targeted delivery of miR-21-5p alleviate postmenopausal osteoporosis via PI3K-AKT pathway · Journal of Nanobiotechnology · 2026
• MicroRNA-29 acutely regulates memory stability, expression of synaptic genes, and DNA methylation in the mouse adult hippocampus · Cellular and Molecular Life Sciences · 2026
• MicroRNAs in HPV ‐Associated Carcinogenesis: Potential Biomarkers in Oropharyngeal and Cervical Cancers · IUBMB Life · 2026
• Integrative analysis of circ_DLGAP4, lncRNA KCNQ1OT1, and the miR-9/SOX7 interaction network in chronic kidney disease progression: a case-control study · Functional & Integrative Genomics · 2026
• Mammal placental phenotypes are predictable from microRNA repertoires. · bioRxiv · 2026
• AGO2 slicing restrains RTL1 to prevent vascular defects and lethal neonatal muscle failure · bioRxiv · 2026

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