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Double-stranded RNA (dsRNA) is a virus-encoded signature capable of triggering intracellular Rig-like receptors (RLR) to activate antiviral signaling, but whether intercellular dsRNA structural reshaping mediated by the N 6 -methyladenosine (m 6 A) modification modulates this process remains largely unknown. Here, we show that, in response to infection by the RNA virus Vesicular Stomatitis Virus (VSV), the m 6 A methyltransferase METTL3 translocates into the cytoplasm to increase m 6 A modification on virus-derived transcripts and decrease viral dsRNA formation, thereby reducing virus-sensing efficacy by RLRs such as RIG-I and MDA5 and dampening antiviral immune signaling. Meanwhile, the genetic ablation of METTL3 in monocyte or hepatocyte causes enhanced type I IFN expression and accelerates VSV clearance. Our findings thus implicate METTL3-mediated m 6 A RNA modification on viral RNAs as a negative regulator for innate sensing pathways of dsRNA, and also hint METTL3 as a potential therapeutic target for the modulation of anti-viral immunity. N 6 -methyladenosine (m 6 A) RNA modification regulates RNA metabolism, and has been implicated in immune regulation. Here, the authors show that the m 6 A methyltransferase, METTL3, translocates into the cytoplasm to increase viral RNA m 6 A modification, decreases viral ds RNA content, and thereby dampens the RIG/MDA5-induced anti-viral immunity.

While N6-methyladenosine (m6A), the most abundant internal modification in eukaryotic mRNA, is linked to cell differentiation and tissue development, the biological significance of m6A modification in mammalian glial development remains unknown. Here, we identify a novel m6A reader, Prrc2a (Proline rich coiled-coil 2 A), which controls oligodendrocyte specification and myelination. Nestin-Cre-mediated knockout of Prrc2a induces significant hypomyelination, decreased lifespan, as well as locomotive and cognitive defects in a mouse model. Further analyses reveal that Prrc2a is involved in oligodendrocyte progenitor cells (OPCs) proliferation and oligodendrocyte fate determination. Accordingly, oligodendroglial-lineage specific deletion of Prrc2a causes a similar phenotype of Nestin-Cre-mediated deletion. Combining transcriptome-wide RNA-seq, m6A-RIP-seq and Prrc2a RIP-seq analysis, we find that Olig2 is a critical downstream target gene of Prrc2a in oligodendrocyte development. Furthermore, Prrc2a stabilizes Olig2 mRNA through binding to a consensus GGACU motif in the Olig2 CDS (coding sequence) in an m6A-dependent manner. Interestingly, we also find that the m6A demethylase, Fto, erases the m6A modification of Olig2 mRNA and promotes its degradation. Together, our results indicate that Prrc2a plays an important role in oligodendrocyte specification through functioning as a novel m6A reader. These findings suggest a new avenue for the development of therapeutic strategies for hypomyelination-related neurological diseases.

Background LncRNA-PACERR plays critical role in the polarization of tissue-associated macrophages (TAMs). In this study, we found the function and molecular mechanism of PACERR in TAMs to regulate pancreatic ductal adenocarcinoma (PDAC) progression. Methods We used qPCR to analyse the expression of PACERR in TAMs and M1-tissue-resident macrophages (M1-NTRMs) which were isolated from 46 PDAC tissues. The function of PACERR on macrophages polarization and PDAC proliferation, migration and invasion were confirmed through in vivo and in vitro assays. The molecular mechanism of PACERR was discussed via fluorescence in situ hybridization (FISH), RNA pull-down, ChIP-qPCR, RIP-qPCR and luciferase assays. Results LncRNA-PACERR was high expression in TAMs and associated with poor prognosis in PDAC patients. Our finding validated that LncRNA-PACERR increased the number of M2-polarized cells and facilized cell proliferation, invasion and migration in vitro and in vivo. Mechanistically, LncRNA-PACERR activate KLF12/p-AKT/c-myc pathway by binding to miR-671-3p. And LncRNA-PACERR which bound to IGF2BP2 acts as an m6A-dependent manner to enhance the stability of KLF12 and c-myc in cytoplasm. In addition, the promoter of LncRNA-PACERR was a target of KLF12 and LncRNA-PACERR recruited EP300 to increase the acetylation of histone by interacting with KLF12 in nucleus. Conclusions This study found that LncRNA-PACERR functions as key regulator of TAMs in PDAC microenvironment and revealed the novel mechanisms in cytoplasm and in nucleus.

Background Dynamic N 6 -methyladenosine (m 6 A) RNA modification generated and erased by N 6 -methyltransferases and demethylases regulates gene expression, alternative splicing and cell fate. Ocular melanoma, comprising uveal melanoma (UM) and conjunctival melanoma (CM), is the most common primary eye tumor in adults and the 2nd most common melanoma. However, the functional role of m 6 A modification in ocular melanoma remains unclear. Methods m 6 A assays and survival analysis were used to explore decreased global m 6 A levels, indicating a late stage of ocular melanoma and a poor prognosis. Multiomic analysis of miCLIP-seq, RNA-seq and Label-free MS data revealed that m 6 A RNA modification posttranscriptionally promoted HINT2 expression. RNA immunoprecipitation (RIP)-qPCR and dual luciferase assays revealed that HINT2 mRNA specifically interacted with YTHDF1. Furthermore, polysome profiling analysis indicated a greater amount of HINT2 mRNA in the translation pool in ocular melanoma cells with higher m 6 A methylation. Results Here, we show that RNA methylation significantly inhibits the progression of UM and CM. Ocular melanoma samples showed decreased m 6 A levels, indicating a poor prognosis. Changes in global m 6 A modification were highly associated with tumor progression in vitro and in vivo. Mechanistically, YTHDF1 promoted the translation of methylated HINT2 mRNA, a tumor suppressor in ocular melanoma. Conclusions Our work uncovers a critical function for m 6 A methylation in ocular melanoma and provides additional insight into the understanding of m 6 A modification.

BackgroundAging is an influential risk factor for progression of both degenerative and oncological diseases of the bone. Osteosarcoma, considered the most common primary mesenchymal tumor of the bone, is a worldwide disease with poor 5-year survival. This study investigated the role of aging-/senescence-induced genes (ASIGs) in contributing to osteosarcoma diagnosis, prognosis, and therapeutic agent prediction.MethodsTherapeutically Applicable Research to Generate Effective Treatments (TARGET), Gene Expression Omnibus (GEO), and The Cancer Genome Atlas (TCGA) were used to collect relevant gene expression and clinical data of osteosarcoma and paracancerous tissues. Patients were clustered by consensus using prognosis-related ASIGs. ssGSEA, ESTIMATE, and TIMER were used to determine the tumor immune microenvironment (TIME) of subgroups. Functional analysis of differentially expressed genes between subgroups, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set variation analyses (GSVAs), was performed to clarify functional status. Prognostic risk models were constructed by univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression. SCISSOR was used to identify relevant cells in osteosarcoma single-cell data for different risk groups. The effect of immunotherapy was predicted based on TIDE scores and chemotherapy drug sensitivity using CTRP and PRISM.ResultsThree molecular subgroups were identified based on prognostic differentially expressed ASIGs. Immunological infiltration levels of the three groups differed significantly. Based on GO and KEGG analyses, differentially expressed genes between the three subgroups mainly relate to immune and aging regulation pathways; GSVA showed substantial variations in multiple Hallmark pathways among the subgroups. The ASIG risk score built based on differentially expressed genes can predict patient survival and immune status. We also developed a nomogram graph to accurately predict prognosis in combination with clinical characteristics. The correlation between the immune activation profile of patients and the risk score is discussed. Through single-cell analysis of the tumor microenvironment, we identified distinct risk-group-associated cells with significant differences in immune signaling pathways. Immunotherapeutic efficacy and chemotherapeutic agent screening were evaluated based on risk score.ConclusionAging-related prognostic genes can distinguish osteosarcoma molecular subgroups. Our novel aging-associated gene signature risk score can be used to predict the osteosarcoma immune landscape and prognosis. Moreover, the risk score correlates with the TIME and provides a reference for immunotherapy and chemotherapy in terms of osteosarcoma.

Cardiac myxoma (CM), a rare primary cardiac tumor, poses significant life-threatening risks. Current CM research has remained largely limited to clinical case observations and pathological analyses, thus restricting its clinical therapeutic impact. Fundamental research should be urgently strengthened to better support future CM treatment strategies. In this work, single-cell sequencing is used to elucidated the intricate cellular composition of the CM microenvironments. The mechanisms of heart myxoma cell growth are investigated via proteomics and organoid models, while our western blot analysis reveals cardiac myxoma’s immune evasion strategies. This study successfully characterizes diverse cell types within the CM microenvironment. Notably, ap-CAF cells are found to effectively recruit immune cells via chemokine secretion, fostering immune microenvironment formation. The work’s pseudotime trajectory analysis also demonstrates that CM tumor cells derive from mesenchymal stem cells. Additionally, this work demonstrated that the glycolysis pathway is significantly activated and fuels CM cell growth. Tumor cells exploit the SIRPα-CD47 immune checkpoint to evade the immune system by inhibiting antigen-presenting cell phagocytosis. Tumor-associated macrophages (TAMs) concurrently assume M2 polarization and suppress autoimmune activity through IL-10 . This research comprehensively examines CM’s microenvironmental cellular architecture, metabolic features, and immune escape mechanisms. These work’s findings not only deepen the current understanding of CM’s biological nature but also offer vital theoretical foundations for developing safer, more effective CM therapies.

Background Aging and its associated neurodegenerative diseases were increasingly recognized as one of the greatest global health threats. Brain aging involved a multitude of pathological changes, including immune inflammation and metabolic dysregulation. Methods We systematically characterized spatiotemporal heterogeneity and dynamic gene expression profiles related to immune and metabolic dysfunction during mouse brain aging. By analyzing differentially expressed genes and conducting functional enrichment and gene set enrichment analysis, we constructed a spatiotemporal transcriptomic atlas of aging‐associated metabolic and immune features. We further performed transcription factor enrichment analysis, regulatory network construction, weighted gene co-expression network analysis, and single-cell deconvolution analysis to further reveal underlying mechanisms. Results Our results showed that, throughout aging, most brain regions underwent widespread immune-inflammatory activation with distinct timing and magnitude: svz exhibited the strongest activation at 26 months, th peaks at 21 months, while olf maintained low immune activation. In terms of metabolic function, different regions responded oppositely to oxidative stress and compensatory mechanisms: mPTP pathway’s genes were significantly upregulated in th but downregulated in cor. Moreover, each brain region possessed its own unique regulatory network, and the H3K27-methyltransferase activity of the PRC2 complex displayed region-dependent age dynamics, suggesting these epigenetic differences (especially ent and olf) might serve as novel targets for anti-aging interventions. Conclusions This work presented a high-resolution spatiotemporal transcriptomic atlas of mouse brain aging, revealed regionally staggered immune activation, contrasted metabolic adaptations, and illustrated PRC2-mediated epigenetic remodeling during brain aging. These insights advanced our understanding of brain aging mechanisms and identified region-specific therapeutic targets for precision interventions in neurodegenerative diseases. Graphical abstract

N 6 -methyladenosine (m 6 A) is the most universal internal RNA modification on messenger RNAs and regulates the fate and functions of m 6 A-modified transcripts through m 6 A-specific binding proteins. Nevertheless, the functional role and potential mechanism of the m 6 A reading proteins in ocular melanoma tumorigenicity, especially cancer stem-like cell (CSC) properties, remain to be elucidated. Herein, we demonstrated that the m 6 A reading protein YTHDF3 promotes the translation of the target transcript CTNNB1 , contributing to ocular melanoma propagation and migration through m 6 A methylation. YTHDF3 is highly expressed in ocular melanoma stem-like cells and abundantly enriched in ocular melanoma tissues, which is related to poor clinical prognosis. Moreover, YTHDF3 is required for the maintenance of CSC properties and tumor initiation capacity in ocular melanoma both in vitro and in vivo. Ocular melanoma cells with targeted YTHDF3 knockdown exhibited inhibitory tumor proliferation and migration abilities. Transcriptome-wide mapping of m 6 A peaks and YTHDF3 binding peaks on mRNAs revealed a key target gene candidate, CTNNB1 . Mechanistically, YTHDF3 enhances CTNNB1 translation through recognizing and binding the m 6 A peaks on CTNNB1 mRNA.

Immunosenescence, the age-related decline in immune function, profoundly impacts cancer progression and therapeutic outcomes by fostering a tumor-promoting microenvironment and impairing immune surveillance. This review delineates eleven molecular hallmarks of immunosenescence, including genomic instability, telomere attrition, epigenetic dysregulation, mitochondrial dysfunction, and chronic inflammation, which collectively drive immune cell dysfunction and systemic immunosuppression. Aging reshapes the tumor microenvironment (TME) through recruitment of immunosuppressive cells, senescence-associated secretory phenotypes (SASP), and metabolic reprogramming, contributing to therapy resistance and poor prognosis in elderly patients. While immunotherapies such as immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell immunotherapy (CAR-T) cells show promise, their efficacy in aging populations is limited by T cell exhaustion, myeloid bias, and altered intercellular communication. Emerging strategies—including senolytics, epigenetic modulators (e.g., histone deacetylase (HDAC) inhibitor), and metabolic interventions (e.g., spermidine, nicotinamide mononucleotide (NMN))—highlight potential avenues to rejuvenate aged immunity. Single-cell multi-omics (single cell RNA-seq, single cell ATAC-seq) further unravel immune cell heterogeneity, revealing tissue-specific chromatin accessibility dynamics and novel targets like interleukin-34 (IL-34) for microglia-mediated neuroinflammation. However, challenges persist in translating preclinical findings to clinical practice, necessitating age-tailored trials and biomarker-driven approaches. By integrating mechanistic insights with translational innovations, this review underscores the urgency of addressing immunosenescence to optimize cancer immunotherapy for aging populations, ultimately bridging the gap between aging biology and precision oncology.