Search Results (203)

Hepatitis B virus (HBV) remains a major global health challenge, with over 296 million people chronically infected worldwide. Despite the availability of antiviral therapies, a functional cure is rarely achieved, highlighting the need for novel therapeutic strategies. RNA 5-methylcytosine (m⁵C) is a pivotal epitranscriptomic mark implicated in RNA stability, transport, and translation. Emerging evidence shows that m⁵C is conserved within HBV RNA and plays critical roles in the viral life cycle. This review provides a comprehensive overview of the molecular mechanisms governing m⁵C deposition and recognition, summarizes recent advances in m⁵C biology, and highlights the emerging role of epitranscriptomic m⁵C regulation in HBV infection. We discuss the identification of HBV-specific m⁵C sites, the functions of key regulatory enzymes, and their interplay in viral RNA stabilization and evasion of innate immune responses. Interplay between m⁵C and other RNA modifications—particularly N6-methyladenosine (m⁶A)—is examined alongside virus-specific m⁵C regulation in EV71, HIV, HCV, EBV, and SARS-CoV-2. Potential links between m⁵C dysregulation and HBV-induced hepatocarcinogenesis are outlined, and emerging therapeutic strategies targeting the m⁵C machinery are highlighted. Together, these insights position the epitranscriptomic landscape as a promising avenue for innovative antiviral strategies. Full article

Neurodegeneration is increasingly recognized not as a linear trajectory of protein accumulation, but as a multidimensional collapse of biological organization—spanning intracellular signaling, transcriptional identity, proteostatic integrity, organelle communication, and network-level computation. This review intends to synthesize emerging frameworks that reposition neurodegenerative diseases (ND) as progressive breakdowns of interpretive cellular logic, rather than mere terminal consequences of protein aggregation or synaptic attrition. The discussion aims to provide a detailed mapping of how critical signaling pathways—including PI3K–AKT–mTOR, MAPK, Wnt/β-catenin, and integrated stress response cascades—undergo spatial and temporal disintegration. Special attention is directed toward the roles of RNA-binding proteins (e.g., TDP-43, FUS, ELAVL2), m6A epitranscriptomic modifiers (METTL3, YTHDF1, IGF2BP1), and non-canonical post-translational modifications (SUMOylation, crotonylation) in disrupting translation fidelity, proteostasis, and subcellular targeting. At the organelle level, the review seeks to highlight how the failure of ribosome-associated quality control (RQC), autophagosome–lysosome fusion machinery (STX17, SNAP29), and mitochondrial import/export systems (TIM/TOM complexes) generates cumulative stress and impairs neuronal triage. These dysfunctions are compounded by mitochondrial protease overload (LONP1, CLPP), UPR maladaptation, and phase-transitioned stress granules that sequester nucleocytoplasmic transport proteins and ribosomal subunits, especially in ALS and FTD contexts. Synaptic disassembly is treated not only as a downstream event, but as an early tipping point, driven by impaired PSD scaffolding, aberrant endosomal recycling (Rab5, Rab11), complement-mediated pruning (C1q/C3–CR3 axis), and excitatory–inhibitory imbalance linked to parvalbumin interneuron decay. Using insights from single-cell and spatial transcriptomics, the review illustrates how regional vulnerability to proteostatic and metabolic stress converges with signaling noise to produce entropic attractor collapse within core networks such as the DMN, SN, and FPCN. By framing neurodegeneration as an active loss of cellular and network “meaning-making”—a collapse of coordinated signal interpretation, triage prioritization, and adaptive response—the review aims to support a more integrative conceptual model. In this context, therapeutic direction may shift from damage containment toward restoring high-dimensional neuronal agency, via strategies that include the following elements: reprogrammable proteome-targeting agents (e.g., PROTACs), engineered autophagy adaptors, CRISPR-based BDNF enhancers, mitochondrial gatekeeping stabilizers, and glial-exosome neuroengineering. This synthesis intends to offer a translational scaffold for viewing neurodegeneration as not only a disorder of accumulation but as a systems-level failure of cellular reasoning—a perspective that may inform future efforts in resilience-based intervention and precision neurorestoration. Full article

Colchicine is commonly prescribed for inflammation and gout, but its nephrotoxicity and underlying mechanisms remain incompletely understood. The objective of this research was to clarify the association between m6A methylation modifications and nephrotoxicity caused by colchicine. A significant decrease in HK2 cell viability was observed following colchicine treatment, and mRNA sequencing (mRNA-seq) revealed the differential expression of genes associated with DNA damage and autophagy. Further methylated RNA immunoprecipitation sequencing (MeRIP-seq) analysis revealed an association between N6-methyladenosine (m6A) modifications and the expression of genes involved in DNA damage and autophagy after colchicine exposure. Molecular docking and a molecular dynamics (MD) analysis identified ZC3H13 as a potential regulator of colchicine-induced cytotoxicity in HK2. Experimental validation confirmed that colchicine induces DNA damage and autophagy in HK2 cells, with ZC3H13 playing a significant role in these processes. In conclusion, the findings suggested that colchicine-induced damage in HK2 cells is associated with changes in m6A methylation levels in target genes and the altered expression of m6A regulator. Full article

Background/Objectives: Messenger RNA (mRNA) modifications regulate key steps in gene expression, including splicing, translation, and stability. Despite over 300 known RNA modifications, the relatively small subset occurring in mRNA remains understudied compared with tRNA and rRNA. This review aims to systematically evaluate 15 known naturally occurring mRNA-specific modifications, rank them by publication frequency, and highlight emerging frontiers in epitranscriptomics, including discovering new naturally occurring mRNA modifications and environmental RNA (eRNA) epitranscriptomics. Methods: We conducted a structured literature review of PubMed-indexed publications to rank mRNA modifications by citation prevalence. Key modifications such as m⁶A, m⁵C, Ψ, and m¹A were analyzed in terms of enzymatic machinery (“writers,” “erasers,” and “readers”), molecular functions, and physiological relevance. We also reviewed technological advances, with a focus on nanopore sequencing for detection of RNA modifications in native and environmental contexts. Results: The modification m⁶A was identified as the most studied mRNA modification, followed by Ψ, m⁵C, and A-to-I editing (inosine). These modifications influence diverse mRNA processes, including translation efficiency, localization, and immune evasion. Cap-specific modifications such as Cap0, Cap1, and Cap2 were also described, highlighting their role in transcript stability and innate immune regulation. Advances in nanopore sequencing have enabled direct detection of RNA modifications and offer promise for eRNA (environmental RNA) surveys. The potential for nanopore sequencing of many other of the 335 known RNA modifications in the MODOMICS database using existing nanopore technologies is also discussed. Conclusions: mRNA modifications represent a critical, yet incompletely mapped, layer of gene regulation. Continued research—especially using nanopore and machine learning technologies—will help uncover their full biological significance. Exploration of eRNA and identifying new mRNA modifications will redefine our understanding of RNA biology. Full article

tRNA modifications are crucial for efficient protein synthesis, impacting codon recognition, tRNA stability, and translation rates. RNA viruses hijack the host’s translational machinery, including the pool of modified tRNA, to translate their own genomes. However, the mismatch between viral and host codon usage can lead to a limited availability of specific tRNA leading to ribosome stalling, posing a significant challenge for efficient protein translation. While some viruses address this challenge through codon optimization, we show here that SARS-CoV-2 (Coronavirus) and the Zika virus (ZIKV; Flavivirus) adopt a different approach, manipulating the host tRNA epitranscriptome. Analysis of codon bias indices confirmed a substantial divergence between viral and host codon usage, revealing a strong preference in viral genes for codons decoded by tRNAs requiring U34 wobble modification. Monitoring tRNA modification dynamics in infected cells showed that both SARS-CoV2 and ZIKV enhance U34 tRNA modifications during infection. Strikingly, impairing U34 tRNAs profoundly impacted viral replication, underscoring the strict reliance of SARS-CoV-2 and ZIKV on manipulating the host tRNA epitranscriptome to support the efficient translation of their genome. Full article

Background/Objectives: Myelodysplastic syndrome (MDS) is a heterogeneous clonal hematopoietic disorder characterized by ineffective hematopoiesis and leukemic transformation risk. Current therapies show limited efficacy, with ~50% of patients failing hypomethylating agents. This review aims to synthesize recent discoveries through an integrated network model and examine translation into precision therapeutic approaches. Methods: We reviewed breakthrough discoveries from the past three years, analyzing single-cell multi-omics technologies, epitranscriptomics, stem cell architecture analysis, and precision medicine approaches. We examined cell-type-specific splicing aberrations, distinct stem cell architectures, epitranscriptomic modifications, and microenvironmental alterations in MDS pathogenesis. Results: Four interconnected mechanisms drive MDS: genetic alterations (splicing factor mutations), aberrant stem cell architecture (CMP-pattern vs. GMP-pattern), epitranscriptomic dysregulation involving pseudouridine-modified tRNA-derived fragments, and microenvironmental changes. Splicing aberrations show cell-type specificity, with SF3B1 mutations preferentially affecting erythroid lineages. Stem cell architectures predict therapeutic responses, with CMP-pattern MDS achieving superior venetoclax response rates (>70%) versus GMP-pattern MDS (<30%). Epitranscriptomic alterations provide independent prognostic information, while microenvironmental changes mediate treatment resistance. Conclusions: These advances represent a paradigm shift toward personalized MDS medicine, moving from single-biomarker to comprehensive molecular profiling guiding multi-target strategies. While challenges remain in standardizing molecular profiling and developing clinical decision algorithms, this systems-level understanding provides a foundation for precision oncology implementation and overcoming current therapeutic limitations. Full article

N6-methyladenosine (m6A) represents the most common and thoroughly investigated RNA modification and exerts essential functions in regulating gene expression through influencing the RNA stability, the translation efficiency, alternative splicing, and nuclear export processes. The rapid development of high-throughput sequencing approaches, including miCLIP and MeRIP-seq, has profoundly transformed epitranscriptomics research. These techniques facilitate the detailed transcriptome-wide profiling of m6A modifications, shedding light on their crucial roles in diverse biological pathways. This review comprehensively examines the identification, mechanisms of regulation, and functional consequences of m6A modifications. It emphasizes their critical roles in physiological contexts, encompassing immune function, neuronal development, and the differentiation of stem cells. Additionally, the review discusses the contributions of m6A dysregulation to pathological conditions, including cancer, neurodegenerative diseases, and disorders of metabolism. We also discuss the development and application of machine-learning algorithms for m6A site prediction, emphasizing the integration of sequence-based, structural, and evolutionary conservation features to enhance the predictive accuracy. Furthermore, the potential of applying the findings from m6A research in precision medicine and drug development is examined. By synthesizing the current knowledge and emerging trends, this review aims to provide a comprehensive understanding of m6A biology and its translational potential, offering new perspectives for future research and therapeutic innovation. Full article

Drought stress is a predominant abiotic constraint adversely affecting global rice (Oryza sativa) production and threatening food security. While the transcriptional and post-transcriptional regulation of drought-responsive pathways has been widely investigated, the emerging field of epitranscriptomics, particularly RNA chemical modifications such as N6-methyladenosine (m⁶A), adds a new dimension to gene regulation under stress. The most prevalent internal modification in eukaryotic messenger RNA influences RNA metabolism by interacting dynamically with enzymes that add, remove, or recognize the modification. Recent studies in rice reveal that m⁶A deposition is not static but dynamically regulated in response to water-deficit conditions, influencing transcript stability, splicing, nuclear export, and translation efficiency of key drought-responsive genes. This review critically synthesizes current findings on the distribution and functional implications of m⁶A and other epitranscriptomic marks (e.g., 5-methylcytosine [m⁵C], pseudouridine [Ψ]) in modulating rice responses to drought. We discuss the regulatory circuitry involving m⁶A effectors such as OsMTA, OsFIP37, and YTH domain proteins and their integration with known drought-signaling pathways including ABA and reactive oxygen species (ROS) cascades. We also highlight emerging high-resolution technologies such as m⁶A-seq, direct RNA sequencing, and nanopore-based detection that facilitate epitranscriptomic profiling in rice. Finally, we propose future directions for translating epitranscriptomic knowledge into crop improvement, including CRISPR/Cas-based modulation of RNA modification machinery to enhance drought tolerance. Full article

Kalanchoe pinnata is used in traditional medicine to treat cancer, as it contains flavonoids and phenols known to regulate key cellular processes associated with cancer. Breast cancer, the most common cancer among women globally, presents ongoing challenges in treatment. The discovery of m⁶A methylation and its regulation by methylosome proteins offers novel therapeutic avenues for cancer management. This study aimed to investigate the cytotoxic and epitranscriptomic effects of an aqueous extract from K. pinnata on MCF-7 (luminal A) and HCC1937 (triple-negative) breast cancer cells. Cell lines were treated with the aqueous K. pinnata extract, characterized by HPLC, for 72 h, followed by an assessment of cytotoxicity and migration. The expression of methylosome components METTL3 and FTO was measured using RT-PCR. m⁶A global methylation was assessed via colorimetry, and molecular docking studies were conducted. The results indicated that only HCC1937 cells exhibited altered migration capacity. This change was correlated in silico with the inhibition of METTL3 by luteolin and quercetin, constituents of the aqueous extract. METTL3, a methyltransferase, was overexpressed by scratch stimuli but was downregulated following K. pinnata treatment in both MCF-7 and HCC1937 cells. The FTO demethylase was overexpressed in both cell lines. In silico analysis suggested an interaction between FTO and compounds such as gallic acid and myricetin. Additionally, m⁶A global methylation decreased in MCF-7 cells but increased in HCC1937 cells, potentially affecting cell migration. Our findings indicate that K. pinnata influences both METTL3 and FTO, altering m⁶A methylation in a cell-type-dependent manner, with HCC1937 cells being particularly sensitive. Further research is required to elucidate the complete molecular mechanism of K. pinnata’s aqueous extract in breast cancer treatment. Full article

Tumor development is mainly marked by the gradual transformation of cells that acquire capacities such as sustained growth signaling, evasion of growth suppression, resistance to cell death, and induction of angiogenesis, achieving replicative immortality and activating invasion and metastasis. How different epigenetic alterations like m¹A, m⁵C, and m⁶A contribute to tumor development is a field that still needs to be investigated. The immune modulators, CD70, CD80, and TIGIT, mainly regulate T-cell activation and consequently the immune evasion of tumors. Here, we explored the presence and the potential consequences of RNA modifications in these regulators in pan-cancer. Our findings highlight the critical role of the m⁶A, m⁵C, and m¹A in regulating CD70, CD80, and TIGIT across multiple solid tumors. By combining epitranscriptomics data with functional enrichment and survival modeling, we show that RNA modification enzymes not only modulate immune-related gene expression but also serve as potential biomarkers for patient prognosis. By constructing a robust four-gene prognostic signature involving YTHDF3, RBM15B, IGF2BP2, and TRMT61A, we demonstrate that RNA modification profiles can accurately stratify patients into risk groups with distinct overall survival outcomes. The performance of this model across eight cancer types underscores the translational promise of epitranscriptomic markers in both mechanistic understanding and personalized oncology. Altogether, our study bridges the gap between the mechanistic regulation of immune checkpoints and their clinical utility, offering novel insights into how the epitranscriptome can be leveraged to improve cancer prognosis and potentially enhance immunotherapeutic strategies. Full article

Negative-sense RNA viruses comprise a wide array of viral families, such as Orthomyxoviridae, Paramyxoviridae, Rhabdoviridae, and Morbillivirus, all of which are adept at inciting significant epidemic outbreaks. Throughout their replication cycle, these viruses engage in a variety of RNA modifications, during both the co-transcriptional and post-transcriptional phases, which are mediated by specific enzymatic activities. These chemical alterations play a critical role in shaping viral fitness, particularly in terms of evading innate immune responses. Key chemical modifications, such as adenosine methylation, 2′-O methylation of nucleosides, and adenosine-to-inosine editing, play critical roles in determining the stability, translational efficiency, and immune recognition of viral RNA. These modifications can reduce the activation of immune sensors, thereby suppressing interferon production and broader antiviral responses. In contrast, certain modifications may enhance immune recognition, which opens avenues for novel vaccine and antiviral strategy development. A comprehensive understanding of these RNA chemical modifications and their implications for virus–host interactions is essential for advancing therapeutic strategies aimed at manipulating innate immunity and optimizing the efficacy of RNA-based vaccines. This review examines the mechanisms and implications of RNA chemical modifications in negative-sense RNA viruses, emphasizing their dual roles in either evading or activating the innate immune system. Full article

Long non-coding RNAs (lncRNAs) are transcripts over 200 nucleotides long that do not encode proteins. Although many lncRNAs remain uncharacterized, they are known to play diverse regulatory roles in gene expression. A group of lncRNAs called natural antisense transcripts can form double-stranded structures with their sense partners due to sequence complementarity. These duplexes can become substrates for A-to-I RNA editing, an epitranscriptomic modification mediated by ADAR enzymes. RNA editing is known to influence transcript splicing, affect the resulting gene expression product or alter RNA stability, all of which can impact cancer cell biology. Here, we show a novel natural antisense transcript, UGGT1-AS1, that we have identified and characterized in terms of its cellular localization and sense partner interactions. Furthermore, we demonstrate that UGGT1-AS1 affects cell proliferation and regulates the stability of the UGGT1 sense transcript. Finally, using publicly available RNA sequencing data, we identify A-to-I RNA editing events in the protein-coding gene UGGT1 and further confirm them by RT-PCR and Sanger sequencing in MCF7 cell lines. We hypothesize that UGGT1-AS1 may act as a triggering factor for the A-to-I RNA editing process in its sense partner. Our findings highlight the regulatory role of UGGT1-AS1 and suggest its involvement in RNA editing and cancer biology. Full article

This review examines the evolutionary trajectory and functional versatility of RNA, beginning with its proposed involvement in the origin of life and culminating in its current application in therapeutic strategies. We explored the complexity of the transcriptome, splicing mechanisms, and the regulatory functions of non-coding RNAs, especially microRNAs. The processes underlying microRNA biogenesis and activity are discussed in the context of their potential as therapeutic tools. Advances in RNA-based technologies have been further illustrated by the development of mRNA vaccines, representing a significant breakthrough in biomedical innovation. Additionally, we explored the growing field of epitranscriptomics—chemical modifications to RNA that modulate its stability, translation, and function—by analyzing the roles of modification enzymes known as writers, erasers, and readers. Focus is given to how these alterations influence immune reactions and guide the strategic development of future modified mRNA vaccines. Collectively, these advances underscore RNA’s multifaceted roles and its transformative potential in the biological and medical sciences. Full article

Osteoarthritis (OA) is a chronic joint disorder characterized by progressive degeneration of articular cartilage, pain, synovial inflammation, and bone remodeling. Post-transcriptional RNA modifications, known as epitranscriptome, are a group of biochemical alterations in the primary RNA transcript that might influence RNA structure, stability, and function. Different kinds of RNA modifications have been recognized, such as methylation, acetylation, pseudouridylation, and phosphorylation. N6-methyladenosine (m6A), 5-methylcytosine (m5C), N7-methylguanosine (m7G), 2′-O-ribose methylation (2′-O-Me), and pseudouridylation (Ψ) are the most prevalent RNA modifications. Recent studies have shown that disruption in these modifications can interfere with gene expression and protein function. Here, we will review all types of RNA modifications and how they contribute to the onset and progression of OA. To the best of our knowledge, this is the first review comprehensively addressing all epitranscriptomic modifications in OA. Full article

Background: Basolateral amygdala (BLA) deep brain stimulation (DBS) has been shown to alleviate the symptoms of post-traumatic stress disorder (PTSD), but the specific mechanisms remain incompletely understood. The hippocampus, a brain region closely connected to the amygdala, plays a key role in the pathological processes of PTSD. The N6-methyladenosine (m⁶A) methylation of RNAs in the hippocampus is known to play a significant role in regulating the brain’s response to stress and emotional disorders. Methods: This study aimed to comprehensively analyze the roles of transcriptome-wide m⁶A modifications of the hippocampus in the BLA DBS treatment of a PTSD mouse model using m⁶A sequencing. Results: Significant alterations in functional connectivity between the ventral hippocampus (vHPC) and BLA were observed in foot shock (FS) mice through functional magnetic resonance imaging (fMRI) analysis. Furthermore, we observed that the expression of the key m⁶A methyltransferase enzyme, METTL3, in the FS and BLA DBS groups was higher than that in the control group. At the same time, both FS and BLA DBS induced the widespread m⁶A methylation of RNAs in the vHPC. Gene ontology (GO) enrichment analysis revealed that FS altered methylation in metabolic, developmental, and cytoskeletal pathways, while BLA DBS targeted metabolic, cell cycle, and neuroplasticity-related genes. Additionally, BLA DBS reversed the aberrant methylation of genes associated with multiple functional pathways induced by FS, including those related to cholinergic transmission, sodium and calcium ion homeostasis, and stress hormone responsiveness. We identified a set of RNAs with methylation changes that were reversed by BLA DBS in the FS vs. Ctrl (control) comparison, including those associated with cholinergic transmission, sodium and calcium ion balance, and stress hormone response. Additionally, we detected several specific BLA DBS-related genes through MeRIP-qPCR, indicating that DBS influences crucial genes linked to calcium signaling and synaptic plasticity. Conclusions: We draw two conclusions from these findings: BLA DBS may alleviate PTSD-like symptoms by reversing FS-induced methylation changes and by altering the methylation levels of crucial genes. These findings indicate that epigenetic m⁶A modifications in the vHPC may play an important role in the amelioration of PTSD using BLA DBS. Full article