Abdollahi M, Malek V, Tanwar VS
… +11 more, Kato M, Lanting L, Rezaei A, Zhang L, Yang L, Pillai RK, Kebrom L, Nandi J, Huang W, Ma K, Natarajan R
Mol Ther Nucleic Acids
· 2026 Mar · PMID 41532014
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The long noncoding RNA (lncRNA) lnc-megacluster (lncMGC) is implicated in diabetic kidney disease and pancreatic islet dysfunction. However, its role in obesity and insulin resistance (IR) is unknown. Herein, we investig...The long noncoding RNA (lncRNA) lnc-megacluster (lncMGC) is implicated in diabetic kidney disease and pancreatic islet dysfunction. However, its role in obesity and insulin resistance (IR) is unknown. Herein, we investigated the regulatory role of lncMGC in obesity and adipose dysfunction using lncMGC knockout-(KO) mice and further determined the translational potential of lncMGC-based therapeutics for obesity using GapmeR antisense oligonucleotides in wild-type and partially humanized-lncMGC mice. We found lncMGC is upregulated in perigonadal white adipose (gWAT) and brown adipose tissues (BAT) from high-fat diet (HFD)-induced obese mice along with increased endoplasmic reticulum stress signaling. Inhibition of lncMGC in mice via genetic ablation or GapmeRs targeting mouse or human lncMGC displayed protective effects against HFD-induced IR, weight gain, and associated adipose dysfunction, with some sex-specific differences. In parallel, key lncMGC targets regulating gWAT and BAT functions were altered. In gWAT, loss of lncMGC either in KO mice or through GapmeR treatment improved angiogenesis and reduced adipocyte hypertrophy and inflammation. In BAT, lncMGC deficiency or inhibition enhanced mitochondrial thermogenesis and mitophagy markers. Collectively, these new findings underscore the pathogenic role of lncMGC in adipose dysfunction and the therapeutic potential of targeting key lncRNAs for obesity and associated metabolic dysfunction.
Wang T, Han R, Hao Z
… +8 more, Cheng X, Li J, Zhai C, Guo J, Wang D, Deng Y, Zhang L, Tan W
Mol Ther Nucleic Acids
· 2026 Mar · PMID 41503581
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Conventional influenza vaccines provide strain-specific immunity, and their production can be affected by egg-culture-adapted mutations. A universal influenza vaccine with conserved antigens and novel vaccine platforms i...Conventional influenza vaccines provide strain-specific immunity, and their production can be affected by egg-culture-adapted mutations. A universal influenza vaccine with conserved antigens and novel vaccine platforms is urgently required. To induce the immune responses toward more conserved epitopes, we generated a multi-antigen influenza mRNA vaccine, lipopolyplex (LPP)-HNH mRNA, coding headless hemagglutinin stem and neuraminidase with three different sequences (HNH-ORI, HNH-E1, or HNH-E2) and delivered by LPP. The immunogenicity and protective efficacy of these single-chain mRNA vaccines against influenza A viruses were evaluated in mice models. Mice exhibited sustained and robust antibody and cellular immune responses against all three LPP-HNH mRNA vaccines, indicating that these vaccines provided mice with broad protection against H1N1, H3N2, or H5N1 influenza viruses. HNH-E1 and HNH-E2 with optimized sequence showed higher protein expression, stronger specific CD4 and CD8 T cell responses, and more effective protection than those of HNH-ORI, owing to their lower minimum free energy and higher codon adaptation index. These results reveal that the LPP-HNH mRNA vaccine encoding conserved antigens with optimized sequences is a promising strategy for the development of universal influenza vaccines.
Mol Ther Nucleic Acids
· 2026 Mar · PMID 41496894
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The gene therapy landscape has evolved substantially in recent years, beginning with the approval of the first adeno-associated virus-based gene therapy, Luxterna, in 2017. Since then, the US FDA has approved nearly 30 n...The gene therapy landscape has evolved substantially in recent years, beginning with the approval of the first adeno-associated virus-based gene therapy, Luxterna, in 2017. Since then, the US FDA has approved nearly 30 new viral gene therapy programs, with notable examples including Zolgensma, Spinraza, Hemgenix, Zynteglo, Lyfgenia, Kymriah, Skysona, and Tecelra. Remarkably, all these products rely on delivery via adeno-associated vectors (AAVs) and lentiviral vectors (LVs). Improvements in viral-mediated gene transfer efficiency and clinical-scale manufacturing, together with immense commercial interest, have greatly propelled the clinical adoption of gene therapy products. In recent years, clustered regularly interspaced short palindromic repeats (CRISPR) and its related Cas proteins (CRISPR-Cas) have made significant advances in gene therapy, offering next-generation approaches for curative gene editing to treat genetic diseases and disorders. In this review, we examine the range of these therapeutics and their viral carriers, focusing primarily on LVs and AAVs. We provide a snapshot of the current status of the field and highlight some of the current challenges in the clinical application of gene therapy, with particular emphasis on viral CRISPR-Cas-based technologies and their future potential.
Rancati S, Pereira RC, Schlich M
… +18 more, Sgroi S, Beatini S, La Rosa L, Giantomasi L, Pelizzoli R, Braccia C, Di Fonzo A, Spattini C, Tuntevski K, Lo Van A, Pons-Espinal M, Palange A, Bajetto A, Daga A, Armirotti A, Florio T, Decuzzi P, De Pietri Tonelli D
Mol Ther Nucleic Acids
· 2025 Dec · PMID 41467122
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Glioblastoma (GBM) is a highly aggressive brain tumor characterized by therapy-resistant glioma stem-like cells (GSCs) and extensive infiltration into surrounding brain tissue. MicroRNAs (miRNAs) are pleiotropic post-tra...Glioblastoma (GBM) is a highly aggressive brain tumor characterized by therapy-resistant glioma stem-like cells (GSCs) and extensive infiltration into surrounding brain tissue. MicroRNAs (miRNAs) are pleiotropic post-transcriptional regulators of oncogenic pathways, but their tumor-suppressive function is frequently lost in GBM. This study explores a multimodal therapeutic approach by restoring a combination of miRNAs to exploit their synergistic effects against GBM. Using patient-derived GBM cells cultured under stem cell-permissive conditions, we demonstrate that miRNA restoration reduces tumor growth, limits invasiveness and stemness, and enhances sensitivity to temozolomide (TMZ). studies in an orthotopic xenograft mouse model of GBM confirm the therapeutic efficacy and low toxicity of the nanoformulated miRNAs, following local injection. Multi-omics and computational analyses on different GBM subtypes reveal that these miRNAs synergistically suppress tumor-promoting extracellular matrix interactions, particularly through the collagen pathway, and downregulate genes associated with GBM progression. The genes downregulated by the miRNAs correlate with glioma grade and poor patient prognosis, further underscoring their therapeutic potential. These findings highlight the promise of combinatorial miRNA therapy as a novel strategy for GBM treatment and suggest new molecular targets for future diagnostic and therapeutic developments.
Xu S, Qi G, Liu R
… +13 more, Liu S, Wang A, Li W, Ruan K, Zhan L, Wang L, Fei C, Zhao J, Zhang X, Yu Q, Xu M, Li J, Han T
Mol Ther Nucleic Acids
· 2025 Dec · PMID 41467121
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Recently, messenger RNA (mRNA)-based vaccine technology has made significant advances in preventing pathogenic microbial infections. The composition and physicochemical properties of lipid nanoparticle (LNP) determine th...Recently, messenger RNA (mRNA)-based vaccine technology has made significant advances in preventing pathogenic microbial infections. The composition and physicochemical properties of lipid nanoparticle (LNP) determine the delivery efficiency of mRNA vaccines. In this study, we synthesized a novel ionizable lipid, C14-192, featuring a 3-oxo-polyamine head group, which was used as a component for LNP to encapsulate and deliver mRNA. Analysis of and expression showed that C14-192-LNP-encapsulated luciferase mRNA exhibited high expression efficiency. To further assess the potential of the C14-192 LNP formulation for vaccine applications, we developed a prophylactic mRNA vaccine against (), based on the conserved and truncated pneumococcal histidine triad protein D (PhtD) and pneumolysin (Ply). The mRNA encoding the fusion construct exhibited the highest expression and secretion levels. In murine model, mRNA vaccine effectively prevented infection and colonization in the lungs and prevented severe lesions. Moreover, the vaccine demonstrated robust cross-protection against multiple serotypes of and provide effective protection against lethal infection. In conclusion, a novel ionizable lipid was successfully synthesized and applied in the development of a new prophylactic vaccine against .
Aghaeipour A, Mitsogiannis M, Fergus C
… +12 more, Tetorou K, Gileadi T, Stojek E, Talavera S, Singh S, Siddle M, Prendeville J, Sokolowska E, Kelly V, Morgan J, Montanaro F, Muntoni F
Mol Ther Nucleic Acids
· 2025 Dec · PMID 41467120
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Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder caused by mutations in the gene that disrupt the production of functional dystrophin proteins. Intellectual disability and neurobehavioral complicatio...Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder caused by mutations in the gene that disrupt the production of functional dystrophin proteins. Intellectual disability and neurobehavioral complications including autism spectrum disorder, attention-deficit disorders, and anxiety cumulatively occur in 33%-43% of the patients due to deficiency of multiple dystrophin isoforms produced in brain. Previous work also identified behavioral abnormalities in the mouse model of DMD. In this work we mapped the expression of the different dystrophin isoforms in different areas of the mouse brain. Next, we determined the behavioral phenotypes that best differentiate (lacking the Dp427 isoform) and wild-type mice. Finally, we investigated the response to intracisternal magna (ICM) injection of exon-skipping phosphorodiamidate morpholino oligomer (PMO) antisense oligonucleotides, which induces skipping of exon 23 and restores the reading frame on these phenotypes. PMO administration led to low, detectable, restoration of dystrophin protein and exon skipping in different brain regions. Treated male mice exhibited a small but significant rescue of their enhanced fear response. We conclude that ICM delivery of PMO leads to low levels of dystrophin restoration, but these levels are sufficient to elicit a modest behavioral phenotype in mice.
Son J, Yoo H, Park J
… +21 more, Park H, Chong SE, Lee J, Kim J, Park E, Bae SH, Kang S, Ban J, Song S, Oh E, Kwak H, Kwon H, Jung J, Lee N, Jung B, Zhang Y, Kang DD, Du S, Shin YK, Dong Y, Jeong JU
Mol Ther Nucleic Acids
· 2025 Dec · PMID 41467118
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[This corrects the article DOI: 10.1016/j.omtn.2025.102697.].[This corrects the article DOI: 10.1016/j.omtn.2025.102697.].
An S, Nomura K, Kobayashi Y
… +3 more, Kimura Y, Abe H, Ui-Tei K
Mol Ther Nucleic Acids
· 2025 Dec · PMID 41467115
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We developed siRMSD, a predictive parameter for off-target effects induced by chemical modifications, to optimize siRNA therapeutics. In RNA interference, small interfering RNA (siRNA) suppresses gene function by degradi...We developed siRMSD, a predictive parameter for off-target effects induced by chemical modifications, to optimize siRNA therapeutics. In RNA interference, small interfering RNA (siRNA) suppresses gene function by degrading mRNA with perfect sequence complementarity, providing therapeutic potential through the targeted inhibition of disease-related genes. However, off-target effects on unintended mRNAs pose a significant challenge to clinical application. While chemical modifications improve nuclease stability and reduce off-target effects, the underlying mechanisms remain unclear. Here, we show that structural distortions caused by chemical modifications determine off-target effects. Modifications, including 2'-O-methoxyethyl, 2'-O-methyl, and 2'-formamido, at positions 2-5 disrupted the A-form RNA duplex on argonaute 2, preventing stable binding to target mRNA. In contrast, modifications at positions 6-8 had minimal impact on off-target effect resulting from changes in thermodynamic stability.
Kuroda T, Yoshioka K, Mon SSL
… +8 more, Katsuyama M, Sato K, Isogai E, Yoshida-Tanaka K, Iwata-Hara R, Yamaguchi T, Obika S, Yokota T
Mol Ther Nucleic Acids
· 2025 Dec · PMID 41467114
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Antisense oligonucleotides (ASOs) represent an attractive therapeutic approach for CNS disorders. However, ASO-induced neurotoxicity, especially late-onset adverse events, remains a crucial issue, leading to failures in...Antisense oligonucleotides (ASOs) represent an attractive therapeutic approach for CNS disorders. However, ASO-induced neurotoxicity, especially late-onset adverse events, remains a crucial issue, leading to failures in clinical applications. This study aims to determine the neurological features and molecular mechanisms of the late-onset neurotoxicity and provide strategies to overcome this toxicity. We initially established neurobehavioral assays of rodent neurotoxicity with intracerebroventricular and intrathecal injections of various gapmer-type ASOs and a neuronal cytotoxicity analysis. Through both and assessments, we identified a site-specific chemical modification, 5'-cyclopropylene (5'-CP), that significantly reduced late-onset neurotoxicity without compromising knockdown activity, providing useful insights into structure-toxicity and structure-activity relationships in ASOs targeting CNS. Additionally, we revealed a toxicity-related mechanism as an elevation of p53-regulated transcripts and paraspeckle protein mislocalization in neuronal cells, which is alleviated through the chemical modifications. Our findings provide mechanistic insights into late-onset ASO-induced neurotoxicity and highlight the potential of optimized chemical modifications to expand the therapeutic window for clinical applications targeting intractable neurological diseases.
Mol Ther Nucleic Acids
· 2025 Dec · PMID 41467113
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MicroRNAs (miRNAs) are small, non-coding RNAs that influence various cellular activities through post-transcriptional gene silencing. Recent research has shown that miRNA modifications, including N6-methyladenosine (m6A)...MicroRNAs (miRNAs) are small, non-coding RNAs that influence various cellular activities through post-transcriptional gene silencing. Recent research has shown that miRNA modifications, including N6-methyladenosine (m6A), 5-methylcytidine (m5C), 2'-O-methylation (Nm), N7-methylguanosine (m7G), pseudouridylation (Ψ), phosphorylation, RNA editing (adenosine to inosine [A to I]), acetylation, and oxidation, play crucial roles in fine-tuning miRNA expression and function. This review examines the impact of nucleotide modifications on miRNA biogenesis, particularly their role in regulating RNA interactions with the Drosha-DiGeorge syndrome critical region 8 (DGCR8) and Dicer complexes, thereby influencing primary miRNA (pri-miRNA) processing, pre-miRNA export, and miRNA maturation. It also examines whether these modifications assist miRNA recognition by RNA-binding proteins (RBPs) in controlling miRNA processing and stability, as well as their impact on miRNA strand selection, target recognition, and the recruitment of regulatory proteins to the miRNA-induced silencing complex (miRISC), which facilitates the silencing of miRNA-targeted messenger RNAs (mRNAs). Additionally, the review discusses the role of miRNA modifications in various human diseases and considers how advanced sequencing technologies and chemical biology approaches enable detailed mapping of these modifications. Furthermore, it provides new insights into the challenges of understanding the dynamic nature of miRNA modifications and their context-dependent effects. It also highlights future directions, including innovative detection methods and epigenetic crosstalk with potential therapeutic applications in human diseases.
Takagi Y, Nishimura T, Aktar S
… +11 more, Katayama D, Takashima K, Kawakita T, Sekiya T, Shingai M, Tanaka H, Akita H, Miyashita Y, Nakamura K, Kouwaki T, Oshiumi H
Mol Ther Nucleic Acids
· 2026 Mar · PMID 41458877
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Proinflammatory cytokines are essential for initiating immune responses; however, excessive or aging-related chronic inflammation impairs immunity and reduces vaccine efficacy. In this study, we developed lipid nanoparti...Proinflammatory cytokines are essential for initiating immune responses; however, excessive or aging-related chronic inflammation impairs immunity and reduces vaccine efficacy. In this study, we developed lipid nanoparticles (LNPs) encapsulating anti-inflammatory microRNA-192 (miR-192) to attenuate inflammation and improve vaccine performance in the elderly. Results revealed that specific proinflammatory cytokines, including interleukin (IL)-6 and tumor necrosis factor (TNF)-α at the vaccination site, diminished antigen-specific antibody production. Notably, miR-192 endowed LNPs with strong anti-inflammatory properties, markedly enhancing vaccine efficacy, especially in aged mice. Transcriptomic analyses demonstrated that miR-192 downregulated multiple pro-inflammatory cytokines, such as senescence-associated secreted phenotype factors, which hinder vaccine responses. Additionally, miR-192 inhibited key components of the JAK-STAT signaling pathway, crucial for cytokine receptor signaling in myeloid cells. Overall, these findings indicate that miR-192 effectively suppresses harmful inflammatory responses, substantially enhancing vaccine efficacy, and highlight the therapeutic potential of the anti-inflammatory microRNA-based adjuvants for improving vaccination outcomes in the elderly.
Ji J, Lipkow E, Anton N
… +3 more, Crucifix C, Eberling P, Laporte J
Mol Ther Nucleic Acids
· 2026 Mar · PMID 41458876
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Lipid nanoparticles (LNPs) are emerging as nonviral vectors for gene therapy; yet, their strong liver tropism and lack of tissue specificity remain limiting. Here, we developed, through rational design, a skeletal muscle...Lipid nanoparticles (LNPs) are emerging as nonviral vectors for gene therapy; yet, their strong liver tropism and lack of tissue specificity remain limiting. Here, we developed, through rational design, a skeletal muscle-targeted delivery platform by functionalizing LNPs with MyomP1, an extracellular conserved peptide derived from the muscle-specific fusogenic protein Myomerger. MyomP1-LNPs were engineered to encapsulate plasmid DNA or mRNA. , MyomP1 conjugation significantly increased transduction efficiency in murine and human myoblasts and myotubes. , MyomP1-LNPs significantly enhanced muscle transduction when delivering DNA cargo, strongly reduced liver accumulation following intramuscular and intravenous mRNA delivery, and attenuated local immune activation. This work demonstrates a ligand-guided strategy to overcome organ-specific barriers in nonviral gene transfer, with improved safety and specificity. It suggests that MyomP1-engineered LNPs hold strong potential to improve therapeutic outcomes for patients with rare muscle diseases, offering a promising alternative to traditional viral gene therapy platforms.
Mol Ther Nucleic Acids
· 2025 Dec · PMID 41438366
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Hunner-type interstitial cystitis (HIC) is a chronic condition marked by persistent pain and inflammation. To elucidate its immunogenetic drivers, we integrated bulk RNA sequencing and single-cell RNA sequencing datasets...Hunner-type interstitial cystitis (HIC) is a chronic condition marked by persistent pain and inflammation. To elucidate its immunogenetic drivers, we integrated bulk RNA sequencing and single-cell RNA sequencing datasets with targeted major histocompatibility complex (MHC) sequencing. Transcriptomic analysis revealed selective expansion of B cells and epithelial cells, with strong enrichment of Epstein-Barr virus (EBV) response signatures. CellChat and NicheNet modeling uncovered bidirectional communication wherein B cells secrete IL-1β, FGF2, LIF, and TNFSF9, activating prostaglandin synthesis, matrix metalloproteinases, and stress genes in epithelial cells. In turn, epithelial BMP4, TGF-β2, and SHH modulate B cell survival. SCENIC regulatory network analysis identified IRF8 as the top B cell regulator; its regulon controls HLA-DQB1, CD40, and CIITA, linking EBV latency to heightened antigen presentation. Among differentially expressed genes, HLA-DQB1 was the most strongly induced in EBV HIC (∼1,000-fold), emerged as the most frequently mutated gene in targeted MHC sequencing, and ranked as a high-confidence IRF8 target. Notably, the evolutionarily constrained variant rs1049133 (A>G) lies within a low-entropy HLA-DQB1 domain, underscoring functional importance. Our integrated analysis supports a model where IRF8-driven, EBV-infected B cells perpetuate HIC via variant HLA-DQB1-mediated antigen presentation and epithelial cytokine loops, highlighting a tractable axis for precision therapy.
Salarpour S, Dourandish F, Salajegheh A
… +1 more, Hashemi S
Mol Ther Nucleic Acids
· 2025 Dec · PMID 41438365
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Although Parkinson's disease (PD) is primarily idiopathic, genetic mutations-accounting for approximately 5%-15% of cases with regional variability-have prompted the development of gene expression modulators, such as oli...Although Parkinson's disease (PD) is primarily idiopathic, genetic mutations-accounting for approximately 5%-15% of cases with regional variability-have prompted the development of gene expression modulators, such as oligonucleotides, to target and reduce alpha-synuclein (α-syn) accumulation. However, challenges in delivering these agents to the brain have limited their therapeutic potential. This study systematically reviews the use of exosomes as delivery systems for oligonucleotides aimed at reducing α-syn aggregation in PD. A comprehensive literature search was conducted using Scopus, Embase, OVID, and ISI Web of Science databases up to January 2022, targeting studies relevant to the subject. Of 904 initial records, five eligible studies were selected. Three utilized transgenic mouse models and two used induced models to simulate PD. All reported a reduction in α-syn aggregation in the midbrain-particularly in the substantia nigra-following treatment with exosome-delivered oligonucleotides. This reduction was associated with decreased neuronal death and improved motor function. No significant toxicity or immune response was reported. Exosome-mediated oligonucleotide delivery appears to be a promising approach to reduce α-syn aggregation, protect dopaminergic neurons, and improve motor symptoms in animal models of PD.
Qiu K, Mao M, Song Y
… +26 more, Duan X, Rao Y, Feng L, Cheng D, Shao X, Liang Y, Jiang C, Huang H, Li L, Wang Y, Li H, Zhu M, Wu S, Xu W, Liu G, Jablonska J, Lang S, Li S, Chen F, Peng X, Zheng Y, Wang H, Liu J, Zhao Y, Song X, Ren J
Mol Ther Nucleic Acids
· 2025 Dec · PMID 41438364
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Messenger RNA (mRNA) vaccines have demonstrated significant potential in cancer immunotherapy by activating both innate and adaptive immunity. However, the detailed cellular and molecular dynamics underpinning these syst...Messenger RNA (mRNA) vaccines have demonstrated significant potential in cancer immunotherapy by activating both innate and adaptive immunity. However, the detailed cellular and molecular dynamics underpinning these systemic immune responses remain incompletely understood. In this study, we characterized the systemic immune landscape following human papillomavirus (HPV)-targeted mRNA-lipid nanoparticle (LNP) vaccination using single-cell RNA sequencing (scRNA-seq) in a murine model of HPV-positive head and neck squamous cell carcinoma (HNSCC). Our study revealed a coordinated remodeling of the systemic immune landscape, involving the tumor microenvironment (TME), tumor-draining lymph nodes (TDLNs), spleen, and blood. Notably, we pioneered a distinct interferon-stimulated gene (ISG) signature across multiple lymphoid subsets in TDLNs, driven by the LNP component, which contributed to rapid, non-antigen-specific immune activation. Additionally, HPV mRNA-LNP vaccination induced an antigen-specific cycling burst of immune cells that mediated tumor control through a systemic coordination of multi-directional differentiation into anti-tumor cell compositions. These findings enhance our understanding of how mRNA-LNP vaccination orchestrates systemic anti-tumor responses and highlight the therapeutic potential of targeting ISG-expressing and cycling immune cells to improve vaccine efficacy, paving the way for future clinical applications in HPV-related cancers.
Mol Ther Nucleic Acids
· 2025 Dec · PMID 41431699
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Epigenetic mechanisms play a crucial role in gene expression regulation during the initiation and progression of cancer. Despite this, over 600 epigenetic regulator (ER) genes, which are responsible for the reading, writ...Epigenetic mechanisms play a crucial role in gene expression regulation during the initiation and progression of cancer. Despite this, over 600 epigenetic regulator (ER) genes, which are responsible for the reading, writing, and erasing of histone and DNA modifications, remain insufficiently characterized in the context of human cancer. In this study, we identified 272 cancer-specific ER genes that were dysregulated in cancer, as determined using a proposed dysregulation score method, based on analysis of over 19,000 paired tumor-normal human samples. Four novel dysregulated ER genes (DEGs), uniquely identified through this method, were shown to have roles in cell proliferation and invasion in melanoma cells. We proposed that loss-of-functional mutations within epigenetic domains may influence the dysregulation of ER genes. Signature scores derived from these DEGs can serve as convenient indicators of patient prognosis in different cancer types. Our findings demonstrated that DEGs in conjunction with immune checkpoints further enhance the prediction performance of the efficiency of cancer immunotherapy compared to using immune checkpoints alone, based on independent cancer cohorts. The DEG list is a valuable resource for translational cancer research, with implications for precision oncology and the development of more effective, individualized epigenetic medicines and therapy.