Search Results (96)

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, in part due to late diagnosis and limited prognostic tools. In recent years, microRNAs, small, non-coding regulators of gene expression, have emerged as key modulators of tumor metabolism, microenvironmental crosstalk, and therapeutic response in HCC. This narrative review synthesizes evidence published from January 2000 through April 2025, focusing on four interrelated themes: (1) miRNA-driven metabolic rewiring; (2) circulating and exosomal miRNAs as diagnostic and (3) predictive biomarkers; (4) miRNA-based therapeutic strategies. We conducted a targeted PubMed search using terms related to HCC, miRNA biology, biomarkers, metabolism, and therapy, supplemented by manual reference mining. Preclinical and clinical studies reveal that loss of tumor-suppressor miRNAs and gain of oncomiRs orchestrate glycolysis, lipid and glutamine metabolism, and stromal-immune remodeling. Circulating miRNA signatures, including single- and multimarker panels, demonstrate diagnostic AUCs up to 0.99 for early-stage HCC and distinguish HCC from cirrhosis more accurately than alpha-fetoprotein. Predictively, miRNAs such as miR-21 and miR-486-3p correlate with sorafenib resistance, while tissue and exosomal miRNAs forecast recurrence and survival after curative therapy. Therapeutic manipulation, restoring tumor-suppressor miRNAs via mimics or AAV vectors and inhibiting oncomiRs with antagomirs or LNA oligonucleotides, yields potent anti-tumor effects in models, affecting cell cycle, apoptosis, angiogenesis, and immune activation. Despite technical and delivery challenges, early-phase trials validate target engagement and inform safety optimization. In this review, we highlight opportunities to integrate miRNA biomarkers into surveillance algorithms and combine miRNA therapeutics with existing modalities, charting a roadmap toward precision-guided management of HCC. Full article

Diabetic kidney disease (DKD) remains the leading cause of end-stage kidney disease (ESKD) globally. Despite advances in our understanding of its pathophysiology, current therapies are often insufficient to stop its progression. In recent years, microRNAs (miRNAs)—small, non-coding RNA molecules involved in post-transcriptional gene regulation—have emerged as critical modulators of key pathogenic mechanisms in DKD, including fibrosis, inflammation, oxidative stress, and apoptosis. Numerous studies have identified specific miRNAs that either exacerbate or mitigate renal injury in DKD. Among them, miR-21, miR-192, miR-155, and miR-34a are associated with disease progression, while miR-126-3p, miR-29, miR-146a, and miR-215 demonstrate protective effects. These molecules are also detectable in plasma, urine, and renal tissue, making them attractive candidates for diagnostic and prognostic biomarkers. Advances in therapeutic technologies such as antagomiRs, mimics, locked nucleic acids, and nanoparticle-based delivery systems have opened new possibilities for targeting miRNAs in DKD. Additionally, conventional drugs, including SGLT2 inhibitors, metformin, and GLP-1 receptor agonists, as well as dietary compounds like polyphenols and sulforaphane, may exert nephroprotective effects by modulating miRNA expression. Recent evidence also highlights the role of gut microbiota in regulating miRNA activity, linking metabolic and immune pathways relevant to DKD progression. Further research is needed to define stage-specific miRNA signatures, improve delivery systems, and develop personalized therapeutic approaches. Modulation of miRNA expression represents a promising strategy to slow DKD progression and improve patient outcomes. Full article

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by inhibiting or degrading messenger RNAs (mRNAs). In ticks, salivary miRNAs are proposed to play key roles in modulating host–vector interactions during blood feeding. Previously, we identified salivary miRNAs in Ornithodoros moubata and Ornithodoros erraticus, major vectors of African swine fever and tick-borne human relapsing fever. In this study, we investigated the regulatory roles of salivary miRNAs in tick biology. Salivary miRNA datasets were re-analysed to identify conserved miRNAs, and putative target genes were predicted using the sialotranscriptomes of both species. In silico predictions were validated through experimental inhibition of specific miRNAs using antagomirs. Knockdown of miR-375 and miR-1 significantly reduced blood intake, oviposition, and fertility, indicating their involvement in feeding and reproductive processes. Silencing miR-252b in O. moubata led to increased mortality, suggesting a critical role in survival. Notably, Metis1 was identified as a likely target of miR-252b, and its dysregulation may underlie the observed lethality in miR-252b-silenced ticks. These findings highlight the functional relevance of salivary miRNAs in tick physiology and host interaction, offering new perspectives for the development of innovative tick control strategies. Full article

Cyclic mechanical stretch has been shown to inhibit myoblast differentiation while promoting proliferation. However, the underlying molecular mechanisms are not well understood. Here, we report that mechanical stretch inhibits the differentiation of mouse primary myoblasts by promoting the cell cycle program and by inhibiting the expression of the myogenic regulator MyoD. Stretch alters the miRNA expression profile as evidenced by miRNA microarray analysis. We identified miR-200c as one of the highly downregulated mechanosensitive miRNAs (mechanomiRs) whose expression level was increased during differentiation. This suggests that mechanomiRs-200c is a myogenic miRNA. Overexpression of mechanomiR-200c revoked the effect of stretch on myoblast differentiation, and the introduction of the mechanomiR-200c antagomir restored the stretch effect. This suggests that stretch blocks differentiation, in part, through mechanomiR-200c. The gene encoding the transcription factor FoxO3 is a known direct target of mechanomiR-200c. Interestingly, MyoD binds to the mechanomiR-200c promoter in differentiating myoblasts, whereas stretch appears to reverse such binding. Our data further demonstrate that the levels of mechanomiR-200c are robustly elevated during the early stage of the muscle repair process in young mice, but not in the injured muscle of aged mice. Overall, we identified a novel pathway, MyoD/mechanomiR-200c/FoxO3a, and the potential mechanism by which stretch inhibits myoblast differentiation. Full article

We first measured the content of chlorfenapyr and tralopyril in silkworm larvae using HPLC, revealing that chlorfenapyr can be biotransformed into tralopyril in silkworms. Then, a differential transcriptomic database of small RNA was constructed through Illumina RNA-Sequencing. qRT-PCR was conducted to determine the expression levels of Bmo-miR-6497-5p and the target CYP450 gene, and Bmo-miR-6497-5p was significantly upregulated in the L3 silkworm larvae 24, 48, and 72 h after they were treated with chlorfenapyr. Furthermore, the target P450 gene CYP337A2 was downregulated at these time points. Dual-luciferase validation revealed that the luciferase activity significantly decreased after Bmo-miR-6497-5p bound to CYP337A2. In addition, miRNA mimics/inhibitor injection and bioassays of chlorfenapyr and tralopyril revealed that the mortality of third silkworm larvae injected with the antagomir of Bmo-miR-6497-5p was significantly increased after exposure to a sublethal concentration of chlorfenapyr. These results imply that Bmo-miR-6497-5p targets CYP337A2, regulating its expression. Also, silkworms increase their tolerance to chlorfenapyr by upregulating Bmo-miR-6497-5p expression, thereby inhibiting the biotransformation of chlorfenapyr to toxic tralopyril catalyzed by CYP337A2. The present study reveals the function of microRNA in silkworm tolerance to chlorfenapyr and improves understanding regarding insecticide resistance in Lepidopteran insects. Full article

MicroRNAs (miRNAs) are small RNA molecules that do not have coding functions but play essential roles in various biological processes. In lung cancer, miRNAs affect the processes of tumor initiation, progression, metastasis, and resistance to treatment by regulating gene expression. Tumor-suppressive miRNAs inhibit oncogenic pathways, while oncogenic miRNAs, known as oncomiRs, promote malignant transformation and tumor growth. These dual roles position miRNAs as critical players in lung cancer biology. Studies in recent years have shown the significant potential of miRNAs as both prognostic and diagnostic biomarkers. Circulating miRNAs in plasma or sputum demonstrate specificity and sensitivity in detecting early-stage lung cancer. Liquid biopsy-based miRNA panels distinguish malignant from benign lesions, and specific miRNA expression patterns correlate with disease progression, response to treatment, and overall survival. Therapeutically, miRNAs hold promise for targeted interventions. Strategies such as miRNA replacement therapy using mimics for tumor-suppressive miRNAs and inhibition of oncomiRs with antagomiRs or miRNA sponges have shown preclinical success. Key miRNAs, including the let-7 family, miR-34a, and miR-21, are under investigation for their therapeutic potential. It should be emphasized that delivery difficulties, side effects, and limited stability of therapeutic miRNA molecules remain obstacles to their clinical use. This article examines the roles of miRNAs in lung cancer by indicating their mechanisms of action, diagnostic significance, and therapeutic potential. By addressing current limitations, miRNA-based approaches could revolutionize lung cancer management, offering precise, personalized, and minimally invasive solutions for diagnosis and treatment. Full article

Asthma and atherosclerosis are chronic conditions with distinct pathophysiologies, but overlapping inflammatory mechanisms that suggest a potential common regulatory framework. MicroRNAs (miRNAs), small non-coding RNA molecules that modulate gene expression post-transcriptionally, could be key players in linking these disorders. This review outlines how miRNAs contribute to the complex interplay between asthma and atherosclerosis, focusing on key miRNAs involved in inflammatory pathways, immune cell regulation and vascular remodeling. We discuss specific miRNAs, such as miR-155, miR-21 and miR-146a, which have been shown to modulate inflammatory cytokine production and T cell differentiation, impacting respiratory and cardiovascular health. The common miRNAs found in both asthma and atherosclerosis emphasize their role as potential biomarkers, but also as therapeutic targets. Understanding these molecular connections may unlock novel approaches for innovative, integrated treatment strategies that address both conditions and may significantly improve patient outcomes. Further research is needed to explore mechanistic pathways and validate the translational potential of miRNA-based interventions in preclinical and clinical settings. Full article

Exosomes can transport regulatory biomolecules and are mediators of cellular signaling among metabolic tissues through endocrine mechanisms. Understanding the pathways and processes underlying exosome-mediated inter-tissue communication is critical for elucidating the molecular pathophysiology of metabolic diseases such as obesity, type 2 diabetes mellitus (T2DM), and cardiovascular disorders. Consequently, these mechanisms represent novel and promising targets for pharmacological regulation. We examined the current knowledge regarding exosome physiology, the mechanisms of interaction with target tissues, and its role in metabolic tissue communication. We also analyzed the secretory profiles of exosomes in metabolic tissues, emphasizing their regulatory roles in adipose tissue, liver, pancreas, skeletal muscle, and the small intestine, while discussing their association with metabolic diseases. In this sense, we propose the exosomal pentad as a novel framework highlighting exosome-mediated inter-organ communication, where exosomes may regulate a metabolic axis involving these tissues. This model aligns with the ominous octet in type 2 diabetes but emphasizes exosomes as key regulators of metabolic homeostasis and potential therapeutic targets. The role of exosomes for the treatment of metabolic diseases emerges as a critical area of pharmacologic exploration. For instance, therapeutic strategies that prevent target tissue binding or expression of cargo molecules such as miRNAs could be designed, using antagomiRs or nanoparticles. Additionally, integrins like αvβ5 on the exosomal membrane can be blocked with monoclonal antibodies or engineered for targeted delivery of therapeutic molecules. Exosomes, critical mediators of inter-organ communication and metabolic regulation, hold potential to design precise molecular-level therapies while minimizing systemic side effects. Full article

Background: The efficacy of programmed cell death 1 (PD-1) or ligand 1 (PD-L1) inhibitors in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients is not satisfactory. Studies have indicated that the ratio of CD8+ tumor infiltration lymphocytes (TILs) was associated with immunotherapy efficacy; however, it was significantly lower in EGFR-mutant than wild type patients. The underlying mechanisms need to be studied. Methods: Database analysis, clinical specimens, small RNA sequencing, and single-cell sequencing were used to analyze miRNA expression and immune cell infiltration. Cell co-culture and flow cytometry were conducted to detect immune cell apoptosis. The mouse model was performed to analyze the influence of miR-651-5p antagomirs on the tumor microenvironment. Results: The miR-651-5p was found to be highly expressed in EGFR-mutant lung adenocarcinoma cell-derived exosomes, which could promote CD8+ T cell apoptosis, while the miR-651-5p inhibitor decreased the ratio of PC9-secreted exosomes and induced apoptosis. Mechanistically, the EGFR signaling pathway promoted the expression of miR-651-5p by activating the transcription factor Fos proto-oncogene (FOS) in EGFR-mutant lung adenocarcinoma cell lines. B-cell lymphoma 2 (BCL2) was the target of miR-651-5p, and miR-651-5p could promote T cell apoptosis by inhibiting BCL2 expression. In addition, the miR-651-5p antagomir increased T cell infiltration and enhanced the efficacy of the PD-1 inhibitor treating the EGFR-mutant lung adenocarcinoma humanized mouse model. Conclusions: EGFR-mutant lung adenocarcinoma promotes T cell apoptosis through exosomal miR-651-5p. miR-651-5p antagonists increase immune cell infiltration and enhance the anti-tumor effect of PD-1 inhibitor, suggesting a new combination therapy to improve the efficacy of immunotherapy in EGFR-mutant NSCLC patients. Full article

Background and Objectives: Atherosclerosis is an inflammatory condition that results in cholesterol accumulating within vessel wall cells. Atherosclerotic cardiovascular disease is the leading cause of mortality worldwide due to this disease being a major contributor to myocardial infarctions and cerebrovascular accidents. Research suggests that cholesterol accumulation occurring precisely within arterial endothelial cells triggers atherogenesis and exacerbates atherosclerosis. Furthermore, inflamed endothelium acts as a catalyst for atherosclerotic development. Therefore, enhancing cholesterol removal specifically in pro-inflammatory endothelial cells may be a potential treatment option for atherosclerosis. While we have previously shown that inhibiting the microRNA guide strand miR-33a-5p within pro-inflammatory endothelial cells increases both ABCA1 expression and apoAI-mediated cholesterol efflux, it is unknown whether inhibiting the miR-33a-3p passenger strand in pro-inflammatory endothelial cells causes similar atheroprotective effects. In this study, this is what we aimed to test. Materials and Methods: We used plasmid transfection to knockdown miR-33a-3p expression within cultured pro-inflammatory immortalized mouse aortic endothelial cells (iMAECs). We compared ABCA1 expression and apoAI-mediated cholesterol efflux within these cells to cultured pro-inflammatory iMAECs transfected with a control plasmid. Results: The knockdown of miR-33a-3p expression within pro-inflammatory iMAECs resulted in a significant increase in ABCA1 mRNA expression. However, the inhibition of miR-33a-3p did not significantly increase ABCA1 protein expression within pro-inflammatory iMAECs. Moreover, we failed to detect a significant increase in apoAI-mediated cholesterol efflux within pro-inflammatory iMAECs from miR-33a-3p knockdown. Conclusions: Our results indicative that the knockdown of miR-33a-3p alone does not enhance ABCA1-dependent cholesterol efflux within pro-inflammatory endothelial cells. To gain any atheroprotective benefit from inhibiting miR-33a-3p within pro-inflammatory endothelium, additional anti-atherogenic strategies would likely be needed in unison. Full article

MicroRNAs (miRNAs) are short sequences of single-stranded non-coding RNAs that target messenger RNAs, leading to their repression or decay. Interestingly, miRNAs play a role in the cellular response to low oxygen levels, known as hypoxia, which is associated with reactive oxygen species and oxidative stress. However, the physiological implications of hypoxia-induced miRNAs (“hypoxamiRs”) remain largely unclear. Here, we investigate the role of miR-210 in brown adipocyte differentiation and thermogenesis. We treated the cells under sympathetic stimulation with hypoxia, CoCl₂, or IOX2. To manipulate miR-210, we performed reverse transfection with antagomiRs. Adipocyte markers expression, lipid accumulation, lipolysis, and oxygen consumption were measured. Hypoxia hindered BAT differentiation and suppressed sympathetic stimulation. Hypoxia-induced HIF-1α stabilization increased miR-210 in brown adipocytes. Interestingly, miR-210-5p enhanced differentiation under normoxic conditions but was insufficient to rescue the inhibition of brown adipocyte differentiation under hypoxic conditions. Although adrenergic stimulation activated HIF-1α signaling and upregulated miR-210 expression, inhibition of miR-210-5p did not significantly influence UCP1 expression or oxygen consumption. In summary, hypoxia and adrenergic stimulation upregulated miR-210, which impacted brown adipocyte differentiation and thermogenesis. These findings offer new insights for the physiological role of hypoxamiRs in brown adipose tissue, which could aid in understanding oxidative stress and treatment of metabolic disorders. Full article

Glioblastoma (GBM) is an aggressive brain cancer with a highly immunosuppressive tumor microenvironment (TME), invariably infiltrated by tumor-associated macrophages (TAMs). These TAMs resemble M2 macrophages, which promote tumor growth and suppress immune responses. GBM cells secrete extracellular vesicles (EVs) containing microRNA-25, which inhibits the cGAS-STING pathway and prevents TAMs from adopting a pro-inflammatory M1 phenotype. This study characterizes antimiR-25/cGAMP nanocomplexes (NCs) for potential therapeutic applications. A particle size analysis revealed a significant reduction upon complexation with antimiR-25, resulting in smaller, more stable nanoparticles. Stability tests across pH levels (4–6) and temperatures (25–37 °C) demonstrated their resilience in various biological environments. Biological assays showed that antimiR-25 NCs interacted strongly with transferrin (Tf), suggesting potential for blood–brain barrier passage. The use of cGAMP NCs activated the cGAS-STING pathway in macrophages, leading to increased type I IFN (IFN-β) production and promoting a shift from the M2 to M1 phenotype. The combined use of cGAMP and antimiR-25 NCs also increased the expression of markers involved in M1 polarization. These findings offer insights into optimizing antimiR-25/cGAMP NCs for enhancing immune responses in GBM. Full article

Atherosclerosis is caused by the accumulation of cholesterol within intimal smooth muscle cells (SMCs) and macrophages. However, the transporter ATP-binding cassette subfamily A, member 1 (ABCA1), can remove cholesterol from these intimal, cells reducing atherosclerosis. Antagomir-mediated inhibition of miR-33a-5p, a microRNA that represses ABCA1 translation, promotes ABCA1-dependent cholesterol efflux and may impede atherosclerosis development. In our previous work, transducing cultured endothelial cells (ECs) with a helper-dependent adenoviral vector (HDAd) that expresses X-motif-tagged anti-miR-33a-5p enhanced antagomir packaging into EC-derived exosomes, which delivered the antagomir to cultured SMCs and macrophages. In this present study, we tested whether in vivo transduction of rabbit carotid artery endothelium can deliver an X-motif-tagged anti-miR-33a-5p to subendothelial cells. Rabbit carotid endothelial cells were transduced in vivo with an HDAd expressing anti-miR-33a-5p either with or without the X-motif (n = 11 arteries per vector). Contralateral carotids received HDAd that express scrambled oligonucleotides. Three days after transduction, the antagomir—without the X-motif—was detected in the intima but not in the media of transduced carotids (p = 0.062). The X-motif antagomir was detected in 82% of the intimal extracts (9 out of 11 carotids) and 27% of medial samples (3 out of 11 carotids, p = 0.031). However, the X-motif did not significantly enhance antagomir delivery to the media (p = 0.214 vs. non-X-motif antagomir). Expression of the antagomirs—with and without the X-motif—was sub-stoichiometric in ECs and SMCs. No antagomir-related changes in miR-33a-5p or ABCA1 expressions were detected. Despite its potential as a therapeutic strategy, our exosome-targeted gene transfer system requires further improvements to enhance antagomir expression and delivery to the subendothelial cells. Full article

Ischemic stroke is a leading cause of disability and mortality worldwide. Recently, increasing evidence implicates microRNAs (miRs) in the pathophysiology of ischemic stroke. Studies have shown that miR-15a/16-1 is abnormally expressed in brains after ischemic stroke, and its upregulation may increase ischemic damage. Given that sex and age are significant modifiers of stroke outcomes, here we investigated whether inhibiting miR-15a/16-1 with antagomirs mitigates cerebral ischemia/reperfusion (I/R) injury in a sex- and age-dependent manner. Young (3 months) and aged (18 months) male and female C57/BL mice underwent 1-h middle cerebral artery occlusion and 3–7 days reperfusion (tMCAO). We administered miR-15a/16-1 antagomir (30 pmol/g) or control antagomir (NC, 30 pmol/g) via tail vein 2 h post-MCAO. Neurobehavioral testing and infarct volume assessment were performed on days 3 and 7. Compared to controls, antagomir treatment significantly improved neurobehavioral outcomes and reduced infarct volume in tMCAO mice at day 7, with the effects being more pronounced in young mice. Notably, young female mice exhibited superior survival and sensorimotor function compared to young male mice. These results were also replicated in a permanent MCAO (pMCAO) mice model. This suggests miR-15a/16-1 antagomir and estradiol may synergistically regulate genes involved in neurovascular cell death, inflammation, and oxidative stress, with sex and age-dependent expression of miR-15a/16-1 and its targets likely underlying the observed variations. Overall, our findings identify miR-15a/16-1 antagomir as a promising therapeutic for ischemic stroke and suggest that sex and age should be considered when developing miR-based therapeutic strategies. Full article

The delay in wound healing caused by chronic wounds or pathological scars is a pressing issue in clinical practice, imposing significant economic and psychological burdens on patients. In particular, with the aging of the population and the increasing incidence of diseases such as diabetes, impaired wound healing is one of the growing health problems. MicroRNA (miRNA) plays a crucial role in wound healing and regulates various biological processes. Our results show that miR–618 was significantly upregulated during the inflammatory phase of wound healing.Subsequently, miR–618 promotes the secretion of pro–inflammatory cytokines and regulates the proliferation and migration of keratinocytes. Mechanistically, miR–618 binds to the target gene–Atp11b and inhibits the PI3K–Akt signaling pathway, inhibiting the epithelial–mesenchymal transition (EMT) of keratinocytes. In addition, the PI3K–Akt signaling pathway induces the enrichment of nuclear miR–618, and miR–618 binds to the promoter of Lin7a to regulate gene transcription. Intradermal injection of miR–618 antagomir around full–thickness wounds in peridermal mice effectively accelerates wound closure compared to control. In conclusion, miR–618 antagomir can be a potential therapeutic agent for wound healing. Full article