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Role of MicroRNAs in Human Diseases: 2nd Edition
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Role of MicroRNAs in Human Diseases: 2nd Edition

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: 20 February 2026 | Viewed by 4646

Special Issue Editor

Dr. Lorenzo F. Sempere

E-Mail Website1 Website2
Guest Editor
Department of Radiology & Precision Health Program, Michigan State University Interdisciplinary Science and Technology Building, Room 218, 766 Service Road, East Lansing, MI 48824, USA
Interests: tissue slide-based microRNA diagnostics; microRNA biology and evolution; cell type-specific activities of microRNAs in oncology with a focus on breast and pancreatic cancer; nanoparticle-based delivery of microRNA activity modulators
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Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous successful Special Issue “Role of MicroRNAs in Human Diseases” (https://www.mdpi.com/journal/ijms/special_issues/F675152Q21).

MicroRNAs are an abundant class of short non-coding RNAs. MicroRNAs regulate gene expression predominantly at the posttranscriptional stage by interacting with partially complementary binding sites on the 3′ UTR of mRNAs of their target genes. Through this mode of regulation and via coordinated interactions with multiple target genes, many miRNAs have been etiologically and mechanistically linked to a variety of human diseases. More than 1900 entries of short non-coding RNA sequences have been registered with miRBase.org for the human genome. Furthermore, 546 of these entries have been curated as bona fide microRNA genes as per mirgenedb.org.

The human miRNome has distinct evolutionary origins; some human microRNAs are conserved in all animals (bilateria), whereas other human microRNAs have more recent origins being specific to eutheria (placental animals), primates, or even restricted to only humans. The evolutionary origin of some miRNAs provides clues of their role in human development, physiology, and pathological processes. Similarly, the tissue- and cell type-specific expression (e.g., muscle cells, neurons, hepatocytes) of some miRNAs offers clues of their biological activity and regulatory networks.

This Special Issue will provide a comprehensive update on the latest findings of human disease–associated miRNAs, with a focus on the clinical application of miRNAs as biomarkers for diagnosis and prognosis, treatment prediction, and miRNA-based therapeutic strategies. Given the broad implication of microRNAs in human diseases, we expect this Special Issue to cover different human diseases from cancer to cardiovascular disease to neurological conditions and degenerative diseases.

We welcome both original research papers and review articles that describe advances in deciphering the etiological and epidemiological links of microRNAs to human diseases, detection methodology and bioinformatics approaches to uncover miRNA signatures, fundamental biology and molecular approaches to determine the mechanistic details of miRNA contribution to human diseases, and diagnostic and therapeutic development to apply this knowledge for the treatment of human diseases in first-in-human clinical trials

Dr. Lorenzo F. Sempere
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • microRNAs, miRNAs, miRs
  • preclinical models
  • target interaction
  • regulatory networks
  • oncology
  • cancer biology
  • cardiovascular disease
  • neurodegenerative conditions
  • diagnostic applications
  • therapeutic development and clinical trials

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Published Papers (6 papers)

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Research

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15 pages, 1666 KB  
Article
A Microarray, Validation, and Gene-Enrichment Approach for Assessing Differentially Expressed Circulating miRNAs in Obese and Lean Heart Failure Patients: A Case–Control Study
by Douglas dos Santos Soares, Amanda Lopes, Mariana Recamonde-Mendoza, Rodrigo Haas Bueno, Raquel Calloni, Nadine Clausell, Santiago Alonso Tobar Leitão and Andreia Biolo
Int. J. Mol. Sci. 2025, 26(19), 9475; https://doi.org/10.3390/ijms26199475 - 27 Sep 2025
Abstract
Obesity is a risk factor associated with cardiovascular diseases that may lead to heart failure (HF). However, in HF, overweight and obese patients have longer survival than underweight patients, a phenomenon known as the obesity paradox. MiRNAs play a fundamental role in gene [...] Read more.
Obesity is a risk factor associated with cardiovascular diseases that may lead to heart failure (HF). However, in HF, overweight and obese patients have longer survival than underweight patients, a phenomenon known as the obesity paradox. MiRNAs play a fundamental role in gene regulation involved in obesity and HF. The main objective of this study was to identify and validate differentially expressed circulating miRNAs in HF–obese and HF–lean patients. This case–control study was carried out in two phases: discovery and validation. In the discovery phase, plasma samples from 20 HF patients and from 10 healthy controls were analyzed using the miRNA 4.0 Affymetrix GeneChip array. Differentially expressed miRNAs were ranked and selected for validation. In this phase, plasma miRNAs -451a, -22-3p, and -548ac from 80 patients and controls were analyzed by qPCR. Target analysis and functional enrichment analysis were performed. When comparing HF–lean and HF–obese groups compared to controls, miRNAs -451a and -22-3p were up-regulated in both discovery and validation phases, while -548ac was down-regulated in the discovery phase and up-regulated in the validation phase, indicating that miRNA changes are independent of obesity. These miRNAs regulate genes and different biological processes associated with metabolic, morphological, and functional outcomes. Full article
(This article belongs to the Special Issue Role of MicroRNAs in Human Diseases: 2nd Edition)
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27 pages, 8654 KB  
Article
Distinct Oxidative Stress Adaptations Driven by the Overexpression of miR-526b, miR-655, and COX-2 in Breast Cancer
by Reid M. Opperman, Sujit Maiti and Mousumi Majumder
Int. J. Mol. Sci. 2025, 26(18), 9103; https://doi.org/10.3390/ijms26189103 - 18 Sep 2025
Viewed by 235
Abstract
Oxidative stress has a dual role in breast cancer, promoting growth at moderate levels while causing cell death at higher levels, such as during therapeutic interventions that increase reactive oxygen species production. Oncogenic microRNAs miR-526b and miR-655 promote aggressive cancer traits—such as proliferation, [...] Read more.
Oxidative stress has a dual role in breast cancer, promoting growth at moderate levels while causing cell death at higher levels, such as during therapeutic interventions that increase reactive oxygen species production. Oncogenic microRNAs miR-526b and miR-655 promote aggressive cancer traits—such as proliferation, migration, invasion, hypoxia response, cancer stem cell properties, and metastasis—via COX-2/EP4/PI3K pathways. These miRNAs and oxidative stress appear to engage in a self-amplifying loop, where miRNA overexpression increases ROS levels, and moderate oxidative stress, in turn, enhances miRNA expression—although the mechanisms are not yet fully understood. This study investigates how overexpressing miR-526b, miR-655, and COX-2 influences breast cancer cell responses to oxidative stress induced by H2O2. We examined cell viability, DNA damage, and transcriptomic changes in MCF7, MCF7-miR526b, MCF7-miR655, and MCF7-COX2 cell lines. Overexpression of COX-2 provided the most significant protection against oxidative stress, decreasing apoptosis and promoting cell cycle progression. Cells with miR-526b and miR-655 exhibited distinct yet overlapping stress responses, including decreased expression of DNA damage markers and alterations in p53 signaling. RNA-sequencing and network analyses identified hub genes involved in redox balance, immune, and metabolic pathways, which may have clinical significance (OAS2, TNF, CACNA1C, CALML5). Overall, these findings suggest that miR-526b, miR-655, and COX-2 play novel roles in promoting resistance to oxidative stress through transcriptional reprogramming in breast cancer; the identified markers could serve as potential biomarkers or therapeutic targets. Full article
(This article belongs to the Special Issue Role of MicroRNAs in Human Diseases: 2nd Edition)
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22 pages, 4280 KB  
Article
The Role of MCM7 and Its Hosted miR-106b-25 Cluster in Renal Cancer Progression
by Katarzyna M. Głuchowska and Bartłomiej Hofman
Int. J. Mol. Sci. 2025, 26(17), 8618; https://doi.org/10.3390/ijms26178618 - 4 Sep 2025
Viewed by 874
Abstract
Renal cancer is among the deadliest human malignancies. MCM7, a cell cycle-regulating protein, is frequently overexpressed in cancers and is associated with hyperproliferation and cancer progression. miR-25-3p, miR-93-5p, and miR-106b-5p form the miR-106b-25 cluster, located within the MCM7 gene, and have previously been [...] Read more.
Renal cancer is among the deadliest human malignancies. MCM7, a cell cycle-regulating protein, is frequently overexpressed in cancers and is associated with hyperproliferation and cancer progression. miR-25-3p, miR-93-5p, and miR-106b-5p form the miR-106b-25 cluster, located within the MCM7 gene, and have previously been reported as upregulated in RCC. This study investigates whether miRNAs from the miR-106b-25 cluster regulate common target genes, enhance one another’s effect, and act synergistically with MCM7 to promote tumor progression. Tissue samples from clear cell RCC (ccRCC) and paired controls were analysed to assess MCM7 expression and genes targeted by the miR-106b-25 cluster. Findings were further validated using the TCGA-KIRC dataset. Functional studies in RCC-derived cell lines were conducted to evaluate the effects of miRNAs on target gene expression, as well as MCM7, and the combined contributions of MCM7 and the miR-106b-25 cluster to renal cancer progression. We demonstrate that MCM7 is upregulated at both transcript and protein levels in RCC, contributing to cancer progression by regulating cell proliferation and caspase-3/7 activity. Furthermore, we identified cancer-related genes aberrantly expressed in ccRCC (BRMS1L, CPEB3, DNAJB9, KIF3B, NFIB, PTPRJ, RBL2) and targeted by members of the miR-106b-25 cluster, suggesting that their dysregulation may be driven by these miRNAs. Inhibition of the miR-106b-25 cluster increases caspase-3/7 activity. These findings demonstrate that both MCM7 and the miR-106b-25 cluster contribute to renal cancer progression. Full article
(This article belongs to the Special Issue Role of MicroRNAs in Human Diseases: 2nd Edition)
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13 pages, 2207 KB  
Article
Regulatory Role of lncRNA MEG3 Silencing on PI3K/GSK3β/Tau Pathway in a High-Glucose-Induced Cell Model
by Lütfiye Ozpak
Int. J. Mol. Sci. 2025, 26(16), 7944; https://doi.org/10.3390/ijms26167944 - 18 Aug 2025
Viewed by 398
Abstract
This study investigated the regulatory role of the long non-coding RNA maternally expressed gene 3 (MEG3) in tau hyperphosphorylation and insulin signaling (PI3K/AKT1/GSK3β) under high-glucose (HG)-induced neurotoxic conditions mimicking Alzheimer’s disease pathology. To explore the function of MEG3 within [...] Read more.
This study investigated the regulatory role of the long non-coding RNA maternally expressed gene 3 (MEG3) in tau hyperphosphorylation and insulin signaling (PI3K/AKT1/GSK3β) under high-glucose (HG)-induced neurotoxic conditions mimicking Alzheimer’s disease pathology. To explore the function of MEG3 within a hyperglycemic (Hyp) model, MEG3 was silenced using small interfering RNA (siRNA) assay, followed by Western blot analysis, qRT-PCR, and network analyses. The siMEG3 + Hyp group had lower levels of AKT1 (0.48-fold) and PI3K (0.52-fold) than did the Hyp group. In the siMEG3 + Hyp group, GSK3β (2.51-fold) and TNFα (2.38-fold) expressions were higher than were those in the Hyp group, while in the siMEG3 group, GSK3β (4.59-fold), microtubule-associated protein TAU (MAPT, TAU) (6.37-fold), interleukin (IL)1β (5.67-fold), IL6 (3.29-fold), and tumor necrosis factor-α (TNFα) (3.06-fold) were all significantly upregulated in comparison to the control group. A higher level of p-tau protein was seen in the siMEG3 group in comparison to the control group, as well as in the siMEG3 + Hyp group in comparison to the Hyp group. Gene ontology analysis following MEG3 administration showed that genes downstream of the PI3K pathway were suppressed, whereas genes regulating the neuroinflammatory response were upregulated. The results suggest that the lncRNA MEG3 may be a promising therapeutic target in HG-induced neurodegenerative AD. Full article
(This article belongs to the Special Issue Role of MicroRNAs in Human Diseases: 2nd Edition)
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Review

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25 pages, 1153 KB  
Review
Exosomal miRNAs: Key Regulators of the Tumor Microenvironment and Cancer Stem Cells
by Shuangmin Wang, Sikan Jin, Jidong Zhang and Xianyao Wang
Int. J. Mol. Sci. 2025, 26(19), 9323; https://doi.org/10.3390/ijms26199323 - 24 Sep 2025
Viewed by 67
Abstract
Exosomes are lipid bilayer vesicles approximately 30–150 nm in diameter that serve as key mediators of intercellular communication. By transporting diverse bioactive molecules, including proteins and nucleic acids, they play a crucial role in tumor initiation and progression. Among their functional cargo, exosomal [...] Read more.
Exosomes are lipid bilayer vesicles approximately 30–150 nm in diameter that serve as key mediators of intercellular communication. By transporting diverse bioactive molecules, including proteins and nucleic acids, they play a crucial role in tumor initiation and progression. Among their functional cargo, exosomal microRNAs (miRNAs) are central to epigenetic regulation and intercellular signaling, significantly influencing tumor biology. This review provides a comprehensive overview of the multifaceted roles of exosomal miRNAs in remodeling the tumor microenvironment (TME) and regulating cancer stem cells (CSCs). Specifically, exosomal miRNAs modulate various immune cells (such as macrophages, T cells, and NK cells) as well as cancer-associated fibroblasts (CAFs), thereby promoting immune evasion, angiogenesis, epithelial–mesenchymal transition (EMT), and metastatic progression. At the same time, they enhance CSC stemness, self-renewal, and therapeutic resistance, ultimately driving tumor recurrence and dissemination. Furthermore, exosome-mediated miRNA signaling acts as a critical force in malignant progression. Finally, we discuss the clinical potential of exosomal miRNAs as diagnostic and prognostic biomarkers, therapeutic targets, and vehicles for targeted drug delivery, highlighting their translational value and future directions in cancer research. Full article
(This article belongs to the Special Issue Role of MicroRNAs in Human Diseases: 2nd Edition)
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28 pages, 1532 KB  
Review
Therapeutic Applications of Poly-miRNAs and miRNA Sponges
by Cynthia Avendaño-Portugal, Mariela Montaño-Samaniego, Raquel Guttman-Bazbaz, Diana M. Bravo-Estupiñan and Miguel Ibáñez-Hernández
Int. J. Mol. Sci. 2025, 26(10), 4535; https://doi.org/10.3390/ijms26104535 - 9 May 2025
Cited by 3 | Viewed by 1597
Abstract
MicroRNAs (miRNAs) are small, non-coding RNA molecules that play crucial roles in regulating gene expression, and their dysregulation is implicated in various human diseases. Over the years, several research groups have identified miRNAs as promising therapeutic targets for intervention. Therapeutic strategies involve either [...] Read more.
MicroRNAs (miRNAs) are small, non-coding RNA molecules that play crucial roles in regulating gene expression, and their dysregulation is implicated in various human diseases. Over the years, several research groups have identified miRNAs as promising therapeutic targets for intervention. Therapeutic strategies involve either overexpression or knockdown of specific miRNAs. This review aims to provide a comprehensive overview of synthetic poly-miRNAs and miRNA sponges, highlighting their therapeutic applications. It begins with an introduction to miRNAs and their role in human diseases, followed by a detailed discussion on synthetic poly-miRNAs and miRNA sponges by exploring their application in cardiovascular, inflammatory, autoimmune, and metabolic disorders, as well as in cancer therapy. Additionally, strategies for targeted delivery, challenges, and limitations of these therapies are addressed. Full article
(This article belongs to the Special Issue Role of MicroRNAs in Human Diseases: 2nd Edition)
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