Stroke is classified as ischemic or hemorrhagic, and there are few effective treatments for either type. Immunologic mechanisms play a critical role in secondary brain injury following a stroke, which manifests as cytokine release, blood-brain barrier disruption, neuronal cell death, and ultimately behavioral impairment. Suppressing the inflammatory response has been shown to mitigate this cascade of events in experimental stroke models. However, in clinical trials of anti-inflammatory agents, long-term immunosuppression has not demonstrated significant clinical benefits for patients. This may be attributable to the dichotomous roles of inflammation in both tissue injury and repair, as well as the complex pathophysiologic inflammatory processes in stroke. Inhibiting acute harmful inflammatory responses or inducing a phenotypic shift from a pro-inflammatory to an anti-inflammatory state at specific time points after a stroke are alternative and promising therapeutic strategies. Identifying agents that can modulate inflammation requires a detailed understanding of the inflammatory processes of stroke. Furthermore, epigenetic reprogramming plays a crucial role in modulating post-stroke inflammation and can potentially be exploited for stroke management. In this review, we summarize current findings on the epigenetic regulation of the inflammatory response in stroke, focusing on key signaling pathways including nuclear factor-kappa B, Janus kinase/signal transducer and activator of transcription, and mitogen-activated protein kinase as well as inflammasome activation. We also discuss promising molecular targets for stroke treatment. The evidence to date indicates that therapeutic targeting of the epigenetic regulation of inflammation can shift the balance from inflammation-induced tissue injury to repair following stroke, leading to improved post-stroke outcomes.

MicroRNAs like miR-146a and miR-29c are potential biomarkers for diabetes, which is linked to brain impairments such as cognitive decline and hippocampal dysfunction due to hyperglycemia and inflammation. This study investigates the effects of high-intensity interval training (HIIT) on hippocampal miR-146a and miR-29c expression and serum TNF-α levels in diabetic rats, highlighting its role in reducing inflammation and improving brain function.

Twenty-four male Wistar rats were divided into four groups: Control (Normal), 1-week diabetes (Diabetes 1 W), 6-week diabetes (Diabetes 6 W), and diabetic HIIT (Diabetes-Exe). Diabetes was induced using streptozotocin (55 mg/kg) and rats with blood glucose > 250 mg/dL were included. HIIT was conducted for six weeks, and hippocampal miR-146a, miR-29c expression, and TNF-α serum levels were assessed using Real-Time PCR and ELISA. TNF-α serum levels were measured as a marker of systemic inflammation.

Diabetic rats exhibited decreased miR-146a and increased miR-29c expression in the hippocampus compared to controls. Additionally, TNF-α serum levels were significantly higher in the diabetic groups, indicating an elevated inflammatory state. HIIT in the Diabetes-Exe group resulted in a non-significant change in miR-29c expression and TNF-α serum levels, accompanied by a significant increase in miR-146a expression compared to the Diabetes 6 W group.

HIIT exercise may help reduce hippocampal neuronal damage in diabetic rats by modulating miR-146a expression, improving blood glucose control, and reducing inflammation. Although HIIT did not significantly alter miR-29c expression, its potential as an effective non-pharmacological strategy for managing diabetic neuropathy complications cannot be excluded.

The significance of microRNAs (miRNAs) in host response to non-tuberculoid mycobacteria like Mycobacterium fortuitum remains nascent. Using zebrafish kidney macrophages (ZFKM), we elucidate a novel function of miR-146a, orchestrated by the TLR-2-PI3K-NF-κB pathway, in M. fortuitum pathogenesis. We demonstrate that miR-146a facilitates anti-inflammatory response by targeting IRAK-1 and TRAF-6 in M. fortuitum-infected ZFKM. Moreover, miR-146a mitigates M1 macrophage activity by suppressing the iNOS-NO axis while enhancing M2-specific TGF-β mRNA expression and subsequent inhibition of M. fortuitum eradication. These findings collectively suggest that miR-146a diminishes macrophage-mediate M. fortuitum clearance. Our study provides novel insights into the intricate interplay between miRNAs and mycobacterial infections. We propose a mechanistic model wherein the TLR-2/NF-κB axis initiates miR-146a expression, which, in turn, suppresses irak-1 and traf-6, fostering the development of M2 macrophages. Consequently, this creates an anti-inflammatory environment conducive to M. fortuitumsurvival. Our findings provide novel insights into the intricate interplay between miRNAs and mycobacterial persistence, a concerning aspect of pathogenesis.

The JAK/STAT signaling pathway plays a crucial role in the release of interferons (IFNs) and the proinflammatory response during SARS-CoV-2 infection, contributing to the cytokine storm characteristic of severe COVID-19 cases. STAT3, a key protein in this pathway, has been implicated in promoting inflammation, making its inhibition a potential therapeutic strategy to mitigate disease severity. Mesenchymal Stem Cell-derived Extracellular Vesicles (MSC-EVs), enriched with immunomodulatory and antiviral miRNAs, offer a promising therapeutic approach by modulating gene expression and regulating inflammatory responses. This study investigates the ability of Lyophilized MSC-EVs to inhibit the JAK/STAT pathway, highlighting their potential application in COVID-19 management.

Male Syrian hamsters were used as an experimental model, housed under controlled laboratory conditions. SARS-CoV-2 (hCoV-19/Egypt/NRC-03/2020) was propagated in Vero E6 cells, and viral titers were determined using plaque assays. Hamsters were intranasally challenged with the virus and treated intraperitoneally with 0.5 mL of lyophilized human Wharton's jelly-derived MSC-extracellular vesicles (MSC-EVs). Histopathological evaluations were performed on lung tissues using H&E, Masson's trichrome, and immunohistochemical staining. Morphometric analyses were conducted to assess lung injury and fibrosis. Western blotting was employed to evaluate protein expression. All procedures adhered to ethical and biosafety guidelines.

The administration of MSC-EVs significantly upregulated the expression levels of miRNA-146a, miRNA-124, miRNA-155, miRNA-29b, miRNA-7, miRNA-145 and miRNA-18a compared to their levels in the COVID-19 group, suggesting a targeted release of miRNA-cargo from the MSC-EVs into the lung tissue of the animals. MSC-EVs impaired the activation of the STAT3/STAT1 signaling pathway and reduced the cytokine storm and coagulopathy associated with COVID-19.

These findings suggest that MSC-EVs have the potential to effectively mitigate the pathogenesis of COVID-19 by targeting the JAK/STAT signaling pathway. Further research is needed to fully understand the mechanisms underlying the therapeutic effects of MSC-EVs and their clinical application in combating the COVID-19 pandemic.

Cold atmospheric plasma (CAP), a redox-regulatory tool, has demonstrated its potency in selectively arresting a wide range of cancer cells, yet its molecular mechanism remains elusive that has largely hindered its clinical translation. Accumulating evidence has implicated the role of CAP in attenuating chronic inflammation in multiple diseases. Using triple negative breast cancer, which is short of effective therapies with little adverse effect, as the tumor model, we reported a synergistic approach to enhance the anti-cancer efficacy of CAP both in vitro and in vivo by coupling it with the mimics of miRNA-146b-5p, a known negative regulator of multiple inflammatory genes in diversified types of cells. Moreover, we identified an innovative path leading to CAP-enabled cancer death involving a SCAF11-mediated competition between FOXO1 and METTL14. This mechanistic model caused enhanced FOXO1 protein degradation and increased pri-miRNA-146b-5p m6A methylation for miRNA-146b-5p maturation. Our findings novel in conceptually proposing a competitive ubiquitination mechanism between two proteins under insufficient E3 ligase supply, and a combinatorial onco-therapeutic modality taking advantages of the unique benefits of CAP and miRNA mimics in alleviating chronic inflammation. Our results have also validated our hypothesis on the role of CAP in selectively targeting transformed cells via attenuating chronic inflammation.

N6-methyladenosine (m6A), one of the most prominent and reversible internal modifications of eukaryotic RNAs, has emerged as a critical regulator of gene expression in various cancers including oral squamous cell carcinoma (OSCC), wherein it shapes the tumor-specific epitranscriptomic gene-regulatory networks. METTL3, the primary m6A RNA methyltransferase, is significantly upregulated in OSCC cells leading to increased global m6A levels. Interestingly, METTL3 positively regulates miRNA biogenesis by modulating the processing of primary miRNAs in a m6A-dependent manner. We identified miR-146a-5p, an oncogenic miRNA as one of the METTL3-regulated miRNAs in OSCC. METTL3-depletion or inhibition of its catalytic activity leads to a reduction of miR-146a-5p and an appreciable accumulation of primary miR-146a in OSCC cells. Functional assays examining the effects of miR-146a-5p inhibition or overexpression confirm its oncogenic role in OSCC pathophysiology. Further, SMAD4, a central transducer in TGF-β signaling, was identified as a miR-146a-5p target. In OSCC cells, SMAD4-depletion exacerbates the oncogenic traits, whereas its overexpression exerts the opposite effect. Additionally, METTL3-depletion dysregulates SMAD4-regulated genes suggesting its potential involvement in SMAD4-dependent TGF-β signaling. Taken together, we report that METTL3, an oncogene regulates the expression of SMAD4, a tumor-suppressor via miR-146a-5p, thus unveiling a novel regulatory axis of METTL3/miR-146a-5p/SMAD4 in OSCC, which can potentially have therapeutic implications.

Dysregulated microRNAs (miRNAs) have significant potential as diagnostic tools for various chronic diseases; however, their therapeutic applications remain largely unexplored. Given their capacity to regulate multiple pathways, miRNAs are promising candidates for treating pleiotropic diseases, such as inflammatory bowel disease (IBD). In our study, we conducted a comprehensive review of the literature of miRNA-146 levels in the inflamed tissues of IBD patients and murine colitis models. Initially, we quantified the expression of miRNA-146a and miRNA-146b in the colons of mice using the dextran sodium sulfate (DSS)-inducedacute model of IBD. We selected miRNA-146a for further study due to its anti-inflammatory properties and potential relevance in IBD treatment. We hypothesized that a macrophage model of inflammation would be well-suited to studying the effects of this miRNA. Subsequently, we investigated the use of lipid nanoparticles (LNPs) for the targeted delivery of miRNA-146a to macrophages, which play a key role in IBD. Our results indicated that miRNA-146a levels increased in the DSS model and LNP-mediated delivery effectively downregulated genes associated with inflammation. These findings highlight the critical role of miRNA-146a in modulating IBD and suggest that LNP-based delivery could be a promising therapeutic strategy for managing inflammatory responses.

Psoriasis and atopic dermatitis (AD) are both chronic inflammatory skin diseases. Their pathogenesis remains incompletely understood. The polarization states of macrophages, as a crucial part of the innate immune system, are influenced by various factors such as cytokines, inflammatory mediators, and epigenetics. Research has demonstrated that macrophages play a "double-edged sword" role in the pathological process of inflammatory skin diseases: they both drive inflammation progression and participate in tissue repair. This article summarizes the roles of macrophages in the inflammatory development and tissue homeostasis of psoriasis and atopic dermatitis. It explores the impact of different factors on macrophages and inflammatory skin diseases. In conclusion, understanding the classification and plasticity of macrophages is crucial for a deeper understanding of the pathogenesis of psoriasis and AD and the development of personalized treatments.

Organ transplantation is the only effective treatment for patients with end-stage organ failure. Although modern immunosuppressive protocols are very effective and improve quality of life, there is still a need for improvements to eliminate their side effects and to induce transplantation tolerance to allografts. The microRNAs (miRNAs) emerged as promising candidates for regulations of several immune functions. The most advanced research of miRNAs documented that several miRNAs form very complex regulatory networks involved in fine and precise mechanisms of multiple pathophysiological process in cells. This review describes the origin of miRNAs and their action mechanisms by which they regulate several immune and cell biology processes, highlighting the fast progress of miRNA research involved in transplant rejection, recent clinical trials, and describing prospects and possible limitations.

Despite the successful development of vaccines and antiviral therapeutics against SARS-CoV-2, its tendency to mutate rapidly has emphasized the need for continued research to better understand this virus's mechanism of pathogenesis and interactions with host signaling pathways. In this study, we sought to explore how the SARS-CoV-2 non-structural protein 13 (Nsp13) helicase, a highly conserved coronavirus protein that is essential for viral replication, influences host biological and cellular processes. Global transcriptomic analyses of Nsp13-transfected A549 cells identified changes in pathways involved in post-transcriptional gene silencing and translational repression by RNA, such as microRNAs (miRNAs). Upon further bioinformatic analyses, we identified miR-146a-mediated signaling pathways to be of interest as this miRNA has been previously linked to the regulation of host inflammation and innate immune responses. We found that miR-146a was induced in Nsp13-transfected cells and observed a corresponding decrease in the gene expression of two miR-146a targets, TRAF6 and IRAK1, which are important upstream regulators of NF-kB activation and IFN signaling. These results suggest that Nsp13-induced miR-146a signaling cascades, namely NF-kB activation and SMAD4 signaling, may provide valuable insight for the development of novel antiviral therapeutics against COVID-19 variants.

Alzheimer's disease is a neurodegenerative disorder characterized by cognitive dysfunction and behavioral abnormalities. Neuroinflammatory plaques formed through the extracellular deposition of amyloid-β proteins, as well as neurofibrillary tangles formed by the intracellular deposition of hyperphosphorylated tau proteins, comprise two typical pathological features of Alzheimer's disease. Besides symptomatic treatment, there are no effective therapies for delaying Alzheimer's disease progression. MicroRNAs (miR) are small, non-coding RNAs that negatively regulate gene expression at the transcriptional and translational levels and play important roles in multiple physiological and pathological processes. Indeed, miR-146a, a NF-κB-regulated gene, has been extensively implicated in the development of Alzheimer's disease through several pathways. Research has demonstrated substantial dysregulation of miR-146a both during the initial phases and throughout the progression of this disorder. MiR-146a is believed to reduce amyloid-β deposition and tau protein hyperphosphorylation through the TLR/IRAK1/TRAF6 pathway; however, there is also evidence supporting that it can promote these processes through many other pathways, thus exacerbating the pathological manifestations of Alzheimer's disease. It has been widely reported that miR-146a mediates synaptic dysfunction, mitochondrial dysfunction, and neuronal death by targeting mRNAs encoding synaptic-related proteins, mitochondrial-related proteins, and membrane proteins, as well as other mRNAs. Regarding the impact on glial cells, miR-146a also exhibits differential effects. On one hand, it causes widespread and sustained inflammation through certain pathways, while on the other hand, it can reverse the polarization of astrocytes and microglia, alleviate neuroinflammation, and promote oligodendrocyte progenitor cell differentiation, thus maintaining the normal function of the myelin sheath and exerting a protective effect on neurons. In this review, we provide a comprehensive analysis of the involvement of miR-146a in the pathogenesis of Alzheimer's disease. We aim to elucidate the relationship between miR-146a and the key pathological manifestations of Alzheimer's disease, such as amyloid-β deposition, tau protein hyperphosphorylation, neuronal death, mitochondrial dysfunction, synaptic dysfunction, and glial cell dysfunction, as well as summarize recent relevant studies that have highlighted the potential of miR-146a as a clinical diagnostic marker and therapeutic target for Alzheimer's disease.

Ischemic stroke (IS) is the leading cause of long-term disability and the second leading cause of death worldwide. It remains a significant clinical problem because only supportive therapies exist, such as thrombolytic agents and surgical thrombectomy, which do not restore function. Understanding the molecular pathogenesis of IS, including dysfunction in oxidative homeostasis, apoptosis, neuroinflammation and neuroprotection, is crucial to developing therapies. Non-coding RNAs (ncRNAs) are master regulators, and one ncRNA that stands out is miR-155, a pro-inflammatory micro-RNA elevated in stroke. This review addresses the biological mechanisms reported in the literature that support using miR-155 as a biomarker and therapeutic agent to treat IS in patients.

Macrophages are integral components of the innate immune system, present in nearly all tissues and organs throughout the body. They exhibit a high degree of plasticity and heterogeneity, participating in immune responses to maintain immune homeostasis. When the immune system loses tolerance, macrophages rapidly proliferate and polarize in response to various signaling pathways within a disrupted microenvironment. The direction of macrophage polarization can be regulated by a variety of factors, including transcription factors, non-coding RNAs, and metabolic reprogramming. Autoimmune diseases arise from the immune system's activation against host cells, with macrophage polarization playing a critical role in the pathogenesis of numerous chronic inflammatory and autoimmune conditions, such as rheumatoid arthritis, systemic lupus erythematosus, immune thrombocytopenic purpura, and type 1 diabetes. Consequently, elucidating the molecular mechanisms underlying macrophage development and function presents opportunities for the development of novel therapeutic targets. This review outlines the functions of macrophage polarization in prevalent autoimmune diseases and the underlying mechanisms involved. Furthermore, we discuss the immunotherapeutic potential of targeting macrophage polarization and highlight the characteristics and recent advancements of promising therapeutic targets. Our aim is to inspire further strategies to restore macrophage balance in preventing and treating autoimmune diseases.

The complex genetic architecture of heritability in multiple sclerosis (MS) remains undisclosed mainly. Epistasis (gene-gene interaction) substantially impacts MS; however, it is largely unexplored, especially among the non-coding RNA genes and their targets. The long non-coding RNA GAS5 exacerbates demyelination and sponges miR-146a and miR-155, impeccable contributors to MS pathogenesis. miR-146a negatively regulates the immune responses by targeting IRAK-1. We investigated the association of epistatic effects and haplotypes of five single nucleotide polymorphisms (SNPs), GAS5 rs2067079, miR-146a rs2910164 and rs57095329, IRAK-1 rs3027898, and miR-155 rs767649, with the risk of MS and its phenotypes. The expression quantitative trait locus (eQTL) associated with these variants was explored through bioinformatics analysis. The study enrolled 116 MS patients and 120 healthy controls. No strong linkage disequilibrium (D' ≥ 0.8) was detected among the studied SNPs. SNP-SNP interactions overlaid an overall magnified risk of MS and its phenotypes compared to the single-locus effects. After adjustment for multiple comparisons, the most significant interactions associated with the risk of overall MS and secondary-progressive MS were rs2067079-rs2910164, rs2910164-rs57095329, and rs3027898-rs767649. The last two former SNP-SNP interactions were highly associated with relapsing-remitting MS risk. The same pattern of interactions, as observed in association with MS risk, was female-specific. The CCAAA haplotype (alleles in the order of rs2067079, rs2910164, rs57095329, rs3027898, and rs767649) was protective against MS risk (CCAAA vs. CGAAT, adjusted OR = 0.14, 95% CI = 0.03-0.69, P = 0.009). Among MS patients, harboring the CGACT and CGAAT haplotypes was more prevalent in females and males, respectively. MS patients having EDSS ≥ 6 had a significantly higher frequency of the CCGCA haplotype than those with EDSS < 6. Functional analysis revealed rs2067079, rs57095329, and rs767649 as strong cis-eQTL regulating multiple genes, particularly in the brain and immune system. We propose that a magnified combined effect of GAS5, miR-146a, IRAK-1, and miR-155 genetic variants via epistatic interactions might impact the risk of MS and its phenotypes and could help in the risk stratification of MS patients.

Osteoarthritis (OA) of the temporomandibular joint (TMJ) is a progressive disease characterized by the progressive destruction of the internal surfaces of the joint. Certain epigenetic biomarkers have been detected in TMJ-OA. We summarized the available evidence on the epigenetic biomarkers in TMJ-OA. There is an increase in the expression of non-coding RNAs related to the degradation of the extracellular matrix, chondrocyte apoptosis, and proinflammatory cytokines, while there is a decrease in the expression of those related to COL2A1, as well as the osteogenic and chondrogenic differentiation of mesenchymal stem cells. Certain methylated genes and histone modifications in TMJ-OA were also identified. In the early stage, DNA methylation was significantly decreased; that is, the expression of inflammation-related genes such as TNF and genes associated with extracellular matrix degradation, such as Adamts, were increased. While in the late stage, there was an increase in the expression of genes associated with the TGF-β and MAPK signaling pathway and angiogenesis-related genes. Although research on the role of epigenetic markers in TMJ-OA is still ongoing, the results here contribute to improving the basis for the identification of accurate diagnostic and prognostic markers and the development of new therapeutic molecules for the prevention and management of TMJ-OA. It also represents a significant advancement in elucidating its pathogenesis.

Epilepsy, a neurological disorder characterized by recurrent seizures, presents significant therapeutic challenges, with roughly 30% of individuals demonstrating resistance to antiepileptic drugs. Drug-resistant epilepsy diminishes patients' quality of life and underscores the critical need for innovative therapeutic approaches. MicroRNAs, small non-coding RNA molecules, have emerged as key regulators in the pathogenesis of epilepsy, influencing neuronal excitability, synaptic plasticity, and neuroinflammatory processes. By targeting multiple genes and pathways involved in epileptogenesis, miRNAs offer promising opportunities for precision medicine. This review explores the dual roles of specific miRNAs in epilepsy, acting as both promoters and inhibitors of pathogenic pathways, and highlights recent advancements in miRNA-based therapeutic delivery systems. State-of-the-art approaches, including lipid nanoparticles, viral vectors, and exosome-based systems, are being developed to address challenges such as blood-brain barrier penetration, targeted delivery, and minimizing systemic side effects. These advancements lay the groundwork for more effective and personalized treatment strategies.

Alzheimer's disease (AD) affects more than 55 million people worldwide, yet current theories cannot fully explain its aetiology. Accordingly, gene expression profiling has been used to provide a holistic view of the biology underpinning AD. Focusing primarily on protein-coding genes, such approaches have highlighted a critical involvement of microglia-related inflammatory processes. Simultaneous investigation of transcriptional regulators and noncoding RNA (ncRNA) can offer further insight into AD biology and inform the development of disease-modifying therapies. We previously described a method for whole transcriptome sampling to simultaneously investigate protein-coding genes and ncRNA. Here, we use this technique to explore transcriptional changes in a murine model of AD (15-month-old APP/PS1 mice). We confirmed the extensive involvement of microglia-associated genes and gene networks, consistent with literature. We also report a wealth of differentially-expressed non-coding RNA - including microRNA, long non-coding RNA, small nuclear and small nucleolar RNA, and pseudogenes - many of which have been overlooked previously. Transcription factor analysis determined that six transcription factors likely regulate gene expression changes in this model (Irf8, Junb, c-Fos, Lmo2, Runx1, and Nfe2l2). We then utilised validated miRNA-target interactions, finding 60 interactions between 15 miRNA and 42 mRNA (messenger RNA) with largely consistent directionality. Furthermore, we found that eight transcription factors (Clock, Lmo2, Runx1, Nfe2l2, Egr2, c-Fos, Junb, and Nr4a1) are likely responsible for the regulation of miRNA expression. Taken together, these data indicate a complex interplay of coding and non-coding RNA, driven by a small number of specific transcription factors, contributing to transcriptional changes in 15-month-old APP/PS1 mice.

Asthma is a complex, multifactorial inflammatory disorder of the airways, characterized by recurrent symptoms and variable airflow obstruction. So far, two main asthma endotypes have been identified, type 2 (T2)-high or T2-low, based on the underlying immunological mechanisms. Recently, extracellular vesicles (EVs), particularly exosomes, have gained increasing attention due to their pivotal role in intercellular communication and distal signaling modulation. In the context of asthma pathobiology, an increasing amount of experimental evidence suggests that EVs secreted by eosinophils, mast cells, dendritic cells, T cells, neutrophils, macrophages, and epithelial cells contribute to disease modulation. This review explores the role of EVs in profiling the molecular signatures of T2-high and T2-low asthma, offering novel perspectives on disease mechanisms and potential therapeutic targets.

Systemic lupus erythematosus (SLE) is a chronic inflammatory illness with heterogeneous clinical manifestations covering multiple organs. Diversified types of medications have been shown effective for alleviating SLE syndromes, ranging from cytokines, antibodies, hormones, molecular inhibitors or antagonists, to cell transfusion. Drugs developed for treating other diseases may benefit SLE patients, and agents established as SLE therapeutics may be SLE-inductive. Complexities regarding SLE therapeutics render it essential and urgent to identify the mechanisms-of-action and pivotal signaling axis driving SLE pathogenesis, and to establish innovative SLE-targeting approaches with desirable therapeutic outcome and safety. After introducing the research history of SLE and its epidemiology, we categorized primary determinants driving SLE pathogenesis by their mechanisms; combed through current knowledge on SLE diagnosis and grouped them by disease onset, activity and comorbidity; introduced the genetic, epigenetic, hormonal and environmental factors predisposing SLE; and comprehensively categorized preventive strategies and available SLE therapeutics according to their functioning mechanisms. In summary, we proposed three mechanisms with determinant roles on SLE initiation and progression, i.e., attenuating the immune system, restoring the cytokine microenvironment homeostasis, and rescuing the impaired debris clearance machinery; and provided updated insights on current understandings of SLE regarding its pathogenesis, diagnosis, prevention and therapeutics, which may open an innovative avenue in the fields of SLE management.

The bulk of RNA produced from the genome of complex organisms consists of a very large number of transcripts lacking protein translational potential and collectively known as noncoding RNAs (ncRNAs). Initially thought to be mere products of spurious transcriptional noise, ncRNAs are now universally recognized as pivotal players in cell regulatory networks across a broad spectrum of biological processes. Owing to their critical regulatory roles, ncRNA dysfunction is closely associated with the etiopathogenesis of various human malignancies, including cancer. As such, ncRNAs represent valuable diagnostic biomarkers as well as potential targets for innovative therapeutic intervention. In this review, we focus on microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), the two most extensively studied classes in the field of ncRNA biology. After outlining key concepts of miRNA and lncRNA biogenesis pathways, we examine their multiple roles in mediating epigenetic regulation of gene expression and chromatin organization. Finally, by providing numerous examples of specific miRNAs and lncRNAs, we discuss how dysregulation of these mechanisms contributes to the onset and/or progression of various human diseases.

In recent years, microRNAs (miRNAs) are potential diagnostic and therapeutic agents for viral infections. Here, we aimed to investigate the expression of microRNAs in the identification and treatment of viral infections. MiRNAs are non-coding molecules that control gene expression and participate in numerous biological processes, including host immunity and pathogen duplication. MiRNAs have played a role in the pathogenesis of various viral infections, such as HIV and HCV. Their presence in the tissues and serum of infected patients has been demonstrated to help predict disease progression, identify disease subtypes, and evaluate treatment responses. Research has shown that miRNAs can detect viral infections by identifying specific miRNAs in serum. For example, miRNA expression profiling was recently used to distinguish between hepatitis C and hepatitis B viral infections precisely. Furthermore, miRNAs can be used to detect the presence of multiple viral infections simultaneously by assessing the expression levels of these miRNAs. Also, miRNAs can differentiate between different genetic variants of the same virus, which is useful for identifying emerging viral strains or drug-resistant ones. MiRNAs have been identified as being a factor in treating viral infections. For example, miRNA mimics have decreased gene expression and halted viral replication in HIV, HCV, and EBV. Moreover, microRNA antagonists have been utilized to inhibit pro-inflammatory cytokines, thereby modulating the immune response and the severity of infections.

Giant cell arteritis (GCA) is a primary systemic vasculitis affecting the elderly, characterized by a granulomatous vessel wall inflammation of large- and medium-sized arteries. The immunopathology of GCA is complex, involving both the innate and adaptive arms of the immune system, where a maladaptive inflammatory-driven vascular repair process ultimately results in vessel wall thickening, intramural vascular smooth muscle cell proliferation, neovascularization and vessel lumen occlusion, which can lead to serious ischemic complications such as visual loss and ischemic stroke. Over the past decade, microRNA (miRNA) dysregulation has been highlighted as an important contributing factor underlying the pathogenesis of GCA. Since current understanding of miRNA involvement in GCA remains largely based on extrapolation of previously determined miRNA functions in vitro or in loss- or gain-of-function studies, an overall insight into the role of miRNA alteration in GCA pathophysiology remains limited. In this narrative review, we summarize the current knowledge on aberrantly expressed miRNAs in GCA and thoroughly discuss the impact of their altered regulatory role in the context of GCA setting. Furthermore, we address challenges and future perspectives in utilization of miRNA-based diagnostic and prognostic biomarkers of GCA in clinical settings.

Cellular phenotypic transformation is a key process that occurs during the development and progression of atherosclerosis. Within the arterial wall, endothelial cells, vascular smooth muscle cells, and macrophages undergo phenotypic changes that contribute to the pathogenesis of atherosclerosis. miRNAs have emerged as potential biomarkers for cellular phenotypic changes during atherosclerosis. Monitoring miR-155-5p, miR-210-3p, and miR-126-3p or 5p levels could provide valuable insights into disease progression, risk of complications, and response to therapeutic interventions. Moreover, miR-92a-3p's elevated levels in atherosclerotic plaques present opportunities for predicting disease progression and related complications. Baseline levels of miR-33a/b hold the potential for predicting responses to cholesterol-lowering therapies, such as statins, and the likelihood of dyslipidemia-related complications. Additionally, the assessment of miR-122-5p levels may offer insights into the efficacy of low-density-lipoprotein-lowering therapies. Understanding the specific miRNA-mediated regulatory mechanisms involved in cellular phenotypic transformations can provide valuable insights into the pathogenesis of atherosclerosis and potentially identify novel therapeutic targets.

Meprin metalloproteases have been implicated in the pathology of ischemia/reperfusion (IR) induced kidney injury. Meprin β proteolytically processes several mediators of cell signaling pathways involved in apoptosis and extracellular matrix metabolism. We previously showed that meprin β cleaves osteopontin (OPN) in vitro. The objective of the current study was to determine how meprin β expression affects OPN and downstream mediators of the OPN-signaling pathway in IR-induced kidney injury.

Ischemia/Reperfusion injury was induced in wild-type (WT) and meprin β knockout (βKO) mice. Blood samples and kidney tissues were obtained at 24 h post-IR. The levels of OPN, Caspase-3, Bcl-2, and NFκB were evaluated using real-time PCR, western blot, and immunohistochemical approaches. Data analysis utilized a combination of 2-way ANOVA and unpaired t test.

OPN mRNA increased in both genotypes at 24 h post-IR. Immunohistochemical staining showed IR-associated increases in the levels of OPN in both genotypes. Additionally, we observed higher levels of OPN in the lumen of proximal tubules in WT only, suggesting that meprin β contributes to enhanced release of OPN into filtrate and ultimately into urine. Immunohistochemical staining showed significant increases in the levels of Caspase-3 and NFκB in select tubules of WT only, while Bcl-2 staining intensity increased significantly in both genotypes at 24 h post-IR.

These findings suggest that meprin β modulates OPN levels in IR-induced kidney injury and impacts apoptotic genes regulated by the OPN signaling pathway.

Not applicable.

Dengue virus (DENV) is a global health threat, with approximately 390 million infections annually, ranging from mild dengue fever to severe dengue hemorrhagic fever and shock syndrome. MicroRNA (miRNA) are crucial post-transcriptional regulators which may regulate host resistance to DENV infection. This study aimed to identify miRNAs involved in natural resistance to DENV infection. Individuals from a dengue-endemic area were classified as susceptible (SD) or resistant (RD) according to their anti-DENV antibody status. RD individuals were seronegative despite high local DENV infection prevalence. Monocytes susceptibility to DENV infection was assessed in vitro. The miRNome profiles of the monocytes from 7 individuals per group were assessed upon mock or DENV-2 infection. The antiviral effect of differentially expressed miRNAs was analyzed using miRNA mimics in HeLa cells followed by infection with DENV-1, DENV-2, DENV-3, and DENV-4 serotypes. We performed RNA-seq on miRNA mimic-transfected cells to identify miRNA-targeted genes interacting with DENV proteins. Monocytes from RD individuals exhibit lower DENV-2 production in vitro. The miRNAs miR-155, miR-132-3p, miR-576-5p were overexpressed in monocytes from RD group upon DENV-2 infection. The transfection of miR-155-5p mimic reduced DENV infection and viral production in HeLa cells, regulating 18 genes interacting with DENV proteins and downregulating target genes involved in interferon response, TP53 regulation, apoptosis, and vesicle trafficking (e.g. HSD17B12, ANXA2). Therefore, we show that monocytes from RD individuals show a distinct miRNA expression profile and reduced viral production. In vitro miR-155-5p upregulation induces an antiviral state, revealing potential therapeutic targets to treat dengue.

Vascular diseases, including atherosclerosis and thrombosis, are leading causes of morbidity and mortality worldwide, often resulting in vessel stenosis that impairs blood flow and leads to severe clinical outcomes. Traditional mechanical interventions, such as balloon angioplasty and bare-metal stents, provided initial solutions but were limited by restenosis and thrombosis. The advent of drug-eluting stents improved short-term outcomes by inhibiting vascular smooth muscle cell proliferation, however, they faced challenges including delayed reendothelialization and late-stage thrombosis.

This review highlights the progression from mechanical to biological interventions in treating vascular stenosis and underscores the need for integrated approaches that combine mechanical precision with regenerative therapies.

To address long-term complications, bioresorbable stents were developed to provide temporary scaffolding that gradually dissolves, yet they still encounter challenges with mechanical integrity and optimal degradation rates. Consequently, emerging therapies now focus on biological approaches, such as gene therapy, extracellular vesicle treatments, and cell therapies, that aim to promote vascular repair at the cellular level. These strategies offer the potential for true vascular regeneration by enhancing endothelialization, modulating immune responses, and stimulating angiogenesis.

Integrating mechanical precision with regenerative biological therapies offers a promising future for treating vascular stenosis. A comprehensive approach combining these modalities could achieve sustainable vascular health.

Clostridioides difficile is a major cause of nosocomial postantibiotic infections, often resulting in severe inflammation and watery diarrhea. Previous studies have highlighted the role of C. difficile flagellin FliC in activating Toll-like receptor 5 and triggering nuclear factor-κB (NF-κB) cell signaling, leading to the release of proinflammatory cytokines. However, the microRNA (miRNA)-mediated regulatory mechanisms underlying the FliC-induced inflammatory response remain unclear.

miRNA expression levels were analyzed in Caco-2 intestinal epithelial cells following FliC stimulation and infection with the epidemic C. difficile R20291 strain or its unflagellated mutant by reverse transcription-quantitative polymerase chain reaction. Chemical inhibitors were used to block NF-κB signaling, and their impact on miR-27a-5p expression was assessed. Knockdown and overexpression experiments with miRNA inhibitor and mimic respectively were conducted to elucidate the functional role of miR-27a-5p in FliC-induced inflammatory responses. Additionally, a mouse model of C. difficile infection was treated with miR-27a-5p to evaluate its therapeutic potential in vivo.

miR-27a-5p showed significant FliC-dependent overexpression in Caco-2 cells. Inhibition of NF-κB signaling suppressed miR-27a-5p overexpression. Knockdown of miR-27a-5p increased NF-κB activation and cytokine production (tumor necrosis factor α and interleukin 8), while its overexpression had the opposite effect. Moreover, miR-27a-5p was overexpressed in the ceca of C. difficile-infected mice, correlating with intestinal interleukin 8 levels. Treatment of infected mice with the miR-27a-5p mimic reduced disease severity and intestinal inflammation.

miR-27a-5p plays a crucial role in regulating C. difficile-induced inflammation, suggesting its potential as a therapeutic target for controlling severe infection. These findings offer valuable insights into potential therapeutic strategies for managing C. difficile infection and associated inflammatory complications.

Rheumatoid arthritis (RA) is a progressive systemic autoimmune disease characterized by chronic inflammation of synovial joints and impaired immunological tolerance. It ultimately results in irreversible joint degeneration. This study aimed to measure Cell-Free DNA (cf-DNA), miR-21, and miR-146a and assess their disease activity levels in RA.

This case-control trial was conducted on 80 subjects (patients and control groups). Cases were categorised into two groups: Group I: 20 cases with active disease and Group II: 20 cases with inactive disease. Group III (control): 40 healthy subjects with matched age and sex. The DAS-28 score was used to assess the RA disease activity. This study demonstrated that miRNA21, miRNA 146a, and cf-DNA significantly increased in both active and inactive groups compared to controls (P-value < 0.001). In addition, there was a significant increase in the active group compared to the inactive group (P-value < 0.001). In the active group, miRNA 146a and cf-DNA exhibited a significant positive correlation with the DAS-28 score and clinical manifestations, including morning stiffness, joint tenderness, and swelling. The linear regression analysis revealed that the primary predictors of miRNA21, miRNA 146a, and cf-DNA levels are the DAS-28 score, ESR, and disease duration.

miRNA 146a can be considered a valuable marker for disease activity in RA patients. Furthermore, cf-DNA is suggested to indicate inflammatory conditions; however, MiR21 did not show a significant association with disease activity.

The present study investigated the relationship between maternal periodontal disease, insulin resistance, activation of inflammatory pathways and epigenetic modifications in adult offspring.

Therefore, female Wistar rats were divided into control and experimental groups. Seven days after the induction of periodontal disease, female rats from both groups were mated with healthy male rats. After weaning, male offspring were divided into control offspring (CN-o) and periodontal disease offspring (PED-o) groups. Body weight was measured at 0-75 days of age. At day 75, the following were measured in the offspring: insulin resistance by the HOMA-IR index; global miRNAs by microtranscriptome array; validation of the selected miRNAs by quantitative real-time PCR expression; interleukin 1 receptor associated kinase 1 (IRAK1) and tumor necrosis factor receptor-associated factor 6 (TRAF6) content in the gastrocnemius muscle tissue (GSM) by western blotting.

Maternal periodontal disease leads to low birth weight (LBW) in the offspring and insulin resistance in adulthood; changes in global miRNA expression (5 miRNAs upregulated and 6 downregulated); and increased protein expression of IRAK1 and TRAF6 in GSM.

These findings demonstrate that maternal periodontal disease causes LBW, insulin resistance, activation of inflammatory pathways, and changes in global miRNA expression.

The clinical syndrome appears as a dysregulated host response to infection that results in life-threatening organ dysfunction known as Sepsis. Sepsis is a serious public health concern where for every five deaths in ICU there is one patient who dies with sepsis worldwide. Sepsis is featured as unbalanced inflammation and immunosuppression which is sustained and profound, increasing patient susceptibility to secondary infections and mortality. microRNAs (miRNAs) play a central role in the control of many biological processes, and the deregulation of their expression has been linked to the development of oncological, cardiovascular, neurodegenerative, and metabolic diseases. In this review, we discuss the role of miRNAs in sepsis pathophysiology. Overall, miRNAs are seen as promising biomarkers, and it has been proposed to develop miRNA-based diagnosis and therapies for sepsis. Yet, the picture is not so straightforward because of miRNAs' versatile and dynamic features. More research is needed to clarify the expression and role of miRNAs in sepsis and promote the use of miRNAs for sepsis management. This study provides an extensive, current, and thorough analysis of the involvement of miRNAs in sepsis. Its purpose is to encourage future research in this area, as tiny miRNAs have the potential to be used for rapid diagnosis, prognosis, and treatment of sepsis.

Recent advancements in microRNAs (miRNAs) research have revealed their key roles in both normal physiological processes and pathological conditions, leading to potential applications in diagnostics and therapeutics. However, the path forward is fraught with several scientific and technical challenges. This review article briefly explores the milestones of the discovery, biogenesis, functions, and application for clinical diagnostic and therapeutic strategies of miRNAs. The potential challenges and future directions are also discussed to fully harness their capabilities.

Breast cancer (BC) is a significant contributor to cancer-related deaths in women, and it has complex connections with obesity and aging. This review explores the interaction between obesity and aging in relation to the development and progression of BC, focusing on the controlling role of microRNAs (miRNAs). Obesity, characterized by excess adipose tissue, contributes to a proinflammatory environment and metabolic dysregulation, which are important in tumor development. Aging, associated with cellular senescence and systemic changes, further exacerbates these conditions. miRNAs, small noncoding RNAs that regulate gene expression, play key roles in these processes, impacting pathways involved in cell proliferation, apoptosis, and cancer metastasis, either as tumor suppressors or oncogenes. Importantly, specific miRNAs are implicated in mediating the impact of obesity and aging on BC. Exploring the regulatory networks controlled by miRNAs provides valuable information on new targets for therapy and predictive markers, demonstrating the potential for using miRNA-based interventions to treat BC in obese and elderly individuals. This review emphasizes the importance of integrated research strategies to understand the complex connections between obesity, aging, and miRNA regulation in BC.

Recently, many studies focused on the billions of native bacteria found inside and all over the human body, commonly known as the microbiota, and its interactions with the eukaryotic host. One of the niches for such microbiota is the gastrointestinal tract (GIT), which harbors hundreds to thousands of bacterial species commonly known as enteric bacteria. Changes in the enteric bacterial populations were linked to various pathologies such as irritable bowel syndrome and obesity. The gut microbiome could affect the health status of individuals. MicroRNAs (miRNAs) are one of the extensively studied small-sized noncoding RNAs (ncRNAs) over the past decade to explore their multiple roles in health and disease. It was proven that miRNAs circulate in almost all body fluids and tissues, showing signature patterns of dysregulation associated with pathologies. Both cellular and circulating miRNAs participate in the posttranscriptional regulation of genes and are considered the potential key regulators of genes and participate in cellular communication. This manuscript explores the unique interplay between miRNAs and enteric bacteria in the gastrointestinal tract, emphasizing their dual role in shaping host-microbiota dynamics. It delves into the molecular mechanisms by which miRNAs influence bacterial colonization and host immune responses, linking these findings to gut-related diseases. The review highlights innovative therapeutic and diagnostic opportunities, offering insights for targeted treatments of dysbiosis-associated pathologies.

Small extracellular vesicles (sEVs) are signalling molecules and biomarkers of cell status that govern a complex intraorgan and interorgan communication system through their cargo. Initially recognized as a waste disposal mechanism, they have emerged as important metabolic regulators. They transfer biological signals to recipient cells through their cargo content, and microRNAs (miRNAs) often mediate their metabolic effects. This review provides a concise overview of sEVs, specifically in the context of obesity-associated chronic inflammation and related metabolic disorders, describing their role as metabolic messengers, identifying their key sites of action and elucidating their mechanisms. We highlight studies that have shaped our understanding of sEV metabolism, address critical questions for future exploration, discuss the use of miRNAs as disease biomarkers and provide insights into the therapeutic potential of sEVs or specific miRNAs for treating metabolic diseases and related disorders in the future.

Chagas disease, caused by Trypanosoma cruzi, is a parasitic zoonosis with significant health impacts, particularly in Latin America. While traditionally associated with vector-borne transmission, increased migration has expanded its reach into urban and non-endemic regions. Congenital transmission has become a critical route of infection, involving intricate maternal-fetal immune interactions that challenge diagnosis and treatment. This review synthesizes findings from three RNA-seq studies that explore the molecular underpinnings of congenital Chagas disease, emphasizing differentially expressed genes (DEGs) implicated in host-pathogen interactions. The DAVID tool analysis highlighted the overexpression of genes associated with the innate immune response, including pro-inflammatory cytokines that drive chemotaxis and neutrophil activation. Additionally, calcium-dependent pathways critical for parasite invasion were modulated. T. cruzi exploits the maternal-fetal immune axis to establish a tolerogenic environment conducive to congenital transmission. Alterations in placental angiogenesis, cellular regeneration, and metabolic processes further demonstrate the parasite's ability to manipulate host responses for its survival and persistence. These findings underscore the complex interplay between the host and pathogen that facilitates disease progression. Future research integrating transcriptomic, proteomic, and metabolomic approaches is essential to unravel the molecular mechanisms underlying congenital Chagas disease, with a particular focus on the contributions of genetic diversity and non-coding RNAs in immune evasion and disease pathogenesis.

Obesity is an emerging health problem worldwide as it is associated with increased risk of cardiovascular, metabolic, mental disorders, and cancer. Therapeutic weight management remains one of the options for the treatment of excess weight and associated comorbidities. In this study, the therapeutic potential of elocalcitol, a fluorinated derivative of vitamin D, was studied on the model of high-fat diet (HFD)-induced obesity in mice.

It was demonstrated that co-administration of elocalcitol in the doses 15 ug/kg (i.p.) twice a week for 16 weeks prevented body weight gain by approximately 15%. The significant retardation in the body weight gain was observed already on the second week of elocalcitol treatment. Administration of elocalcitol also reduced visceral and epididymal fat accumulation by 55% and 35%, respectively, metabolic syndrome development, and lipid droplets accumulation in the liver of mice exposed to HFD. In contrast, the administration of cholecalciferol (vitamin D)-a precursor to calcitriol, the biologically active form of vitamin D, did not affect significantly the signs of obesity and metabolic syndrome, suggesting that the anti-obese effects of elocalcitol are not related to the canonical vitamin D receptor (VDR). Further studies have demonstrated that the preventive effect of elocalcitol is associated with the decreased levels of sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) and upregulation insulin-inducing gene-1 (Insig1) mRNA expression suggesting that the anti-obese effect of elocalcitol is mediated via inhibition of SREBP-mediated lipogenesis. We also demonstrated that elocalcitol prevents an increase in the expression of proinflammatory cytokines such as interleukin-1 beta (Il1b), tumor necrosis factor-alpha (Tnf), and interleukin-18 (Il18), and this effect was associated with upregulation of microRNA-146a (miR-146a). Deletion of the miR-146a gene reduced the anti-obese effects of elocalcitol and prevented its actions on the SCAP levels. The data indicate that elocalcitol's reduction of SCAP is at least partly mediated by miR-146a modulation.

The study demonstrates that elocalcitol prevents HFD-induced obesity and metabolic syndrome in mice, likely by inhibiting SREBP-mediated lipogenesis and upregulating miR-146a. These findings provide valuable insights into the anti-obesity mechanisms of fluorinated D-vitamin analogs and suggest potential therapeutic strategies for obesity prevention.

The prevalence of osteoarthritis (OA) notably surges with age and weight gain. The most common clinical therapeutic drugs are painkillers, yet they cannot impede the deteriorating course of OA. Thus, understanding OA's pathogenesis and devising effective therapies is crucial. It is generally recognized that inflammation, pyroptosis, and OA progression are tightly linked. The activation of NLRP3 inflammasome can lead to the discharge of the pro-inflammatory cytokines Interleukin-1β and IL-18, intensifying subsequent inflammatory reactions and promoting OA development. Conversely, the imbalance caused by deacetylase-regulated NLRP3 inflammasome underlies the chronic mild inflammation related to degenerative diseases. Therefore, this article expounds on the mechanism of OA pathogenesis and the role of histone deacetylases (HDACs) in NLRP3 inflammasome-triggered OA, and illustrates the application of HDAC inhibitors in OA, striving to provide more insights into novel OA treatment approaches.

MicroRNAs (miRNAs) and transfer RNA-derived stress-induced RNAs (tiRNAs) have emerged as crucial players in the post-transcriptional regulation of gene expression in various cellular processes, including immunity and host defense against infections. In recent years, increasing evidence has highlighted their complex role in influencing the host response during viral and bacterial infections. miRNAs have been shown to play multiple roles in host-pathogen interaction like TLR activation and altered disease virulence during bacterial infections. In the context of viral infections, miRNAs are involved in regulating viral replication, pathogenesis, and immune evasion. Similarly, tiRNAs have recently emerged as novel players in bacterial and viral infections such as modulating bacterial growth, adaptation to stress conditions, host antiviral responses, and impacting viral replication and pathogenesis. This review provides a comprehensive analysis of the potential of miRNA expression profiles as diagnostic biomarkers to differentiate between bacterial and viral infections. Further discusses the key pathways through which small RNAs regulate bacterial and viral infection-related diseases.

Cardiac hypertrophy is an adaptive response to pressure or volume overload such as hypertension and ischemic heart diseases. Sustained cardiac hypertrophy eventually leads to heart failure. The pathophysiological alterations of hypertrophy are complex, involving both cellular and molecular systems. Understanding the molecular events that inhibit or repress cardiac hypertrophy may help identify novel therapeutic strategies. Increasing evidence has indicated that extracellular vesicle (EV)-derived microRNAs (miRNAs) play a significant role in the development and progression of cardiac hypertrophy. In this review, we briefly review recent advancements in EV research, especially on biogenesis, cargoes and its role in cardiac hypertrophy. We then describe the latest findings regarding EV-derived miRNAs, highlighting their functions and regulatory mechanisms in cardiac hypertrophy. Finally, the potential role of EV-derived miRNAs as targets in the diagnosis and treatment of cardiac hypertrophy will be discussed.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by binding to the 3'-untranslated regions of target mRNAs, influencing various biological processes at the post-transcriptional level. Identifying miRNA transcription start sites (TSSs) and transcription factors' (TFs) regulatory roles is crucial for elucidating miRNA function and transcriptional regulation. miRStart 2.0 integrates over 4500 high-throughput datasets across five data types, utilizing a multi-modal approach to annotate 28 828 putative TSSs for 1745 human and 1181 mouse miRNAs, supported by sequencing-based signals. Over 6 million tissue-specific TF-miRNA interactions, integrated from ChIP-seq data, are supplemented by DNase hypersensitivity and UCSC conservation data, with network visualizations. Our deep learning-based model outperforms existing tools in miRNA TSS prediction, achieving the most overlaps with both cell-specific and non-cell-specific validated TSSs. The user-friendly web interface and visualization tools make miRStart 2.0 easily accessible to researchers, enabling efficient identification of miRNA upstream regulatory elements in relation to their TSSs. This updated database provides systems-level insights into gene regulation and disease mechanisms, offering a valuable resource for translational research, facilitating the discovery of novel therapeutic targets and precision medicine strategies. miRStart 2.0 is now accessible at https://awi.cuhk.edu.cn/∼miRStart2.