5-methylcytosine methylation of MALAT1 promotes resistance to sorafenib in hepatocellular carcinoma through ELAVL1/SLC7A11-mediated ferroptosis

Drug Resistance Updates, Journal Year: 2024, Volume and Issue: 78, P. 101181 - 101181

Published: Dec. 4, 2024

Emerging evidence demonstrates that long non-coding RNAs (lncRNAs) play a crucial role in sorafenib resistance hepatocellular carcinoma (HCC), and lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is dysregulated sorafenib-resistant HCC cells. However, the underlying regulatory mechanisms of MALAT1 cells remain unclear. In present study, we demonstrated 5-methylcytosine (m5C) methylation catalyzed by NSUN2 ALYREF contributed to RNA stability upregulation MALAT1. The NSUN2/ALYREF/MALAT1 signaling axis was activated cells, inhibited sorafenib-induced ferroptosis drive resistance. Mechanistically, maintained mRNA SLC7A11 directly binding ELAVL1 stimulating its cytoplasmic translocation. Furthermore, explored new synergetic strategy for treatment combining inhibitor MALAT1-IN1 with sorafenib. results significantly enhanced efficacy both vitro vivo. Collectively, our work brings insights into epigenetic offers an alternative therapeutic targeting patients.

Language: Английский

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Methyltransferase-like 3 mediates m6A modification of heme oxygenase 1 mRNA to induce ferroptosis of renal tubular epithelial cells in acute kidney injury

Free Radical Biology and Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Acute kidney injury (AKI) involves a series of syndromes characterized by rapid increase in creatinine levels. Ferroptosis, as an iron-dependent mode programmed cell death, reportedly participates the pathogenesis AKI. Methyltransferase-like 3 (METTL3)-mediated m6A modification has been recently associated with various diseases; however, mechanism METTL3 crosstalk molecules involved ferroptosis is not clearly understood. Here, we investigated between METTL3-mediated and was elevated patients AKI, FA-AKI mice, TBHP-stimulated TCMK-1 cells. Inhibition expression vivo vitro alleviated damage renal tubular MeRIP sequencing showed that heme oxygenase 1 (Hmox1/HO-1) target. RIP-qPCR indicated anti-insulin-like growth factor 2 mRNA binding protein 3(IGF2BP3) could be used reader to bind methylated site Hmox1 maintain its stability. knockdown reduced accumulation iron ions ferroptosis. mediates maintains stability IGF2BP3-dependent manner, which causes overload epithelial cells, leading

Language: Английский

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m6A epitranscriptomic modification in hepatocellular carcinoma: implications for the tumor microenvironment and immunotherapy

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 17, 2025

Hepatocellular carcinoma (HCC) is the most prevalent primary liver malignancy and a leading cause of cancer-related deaths globally. The asymptomatic progression early-stage HCC often results in diagnosis at advanced stages, significantly limiting therapeutic options worsening prognosis. Immunotherapy, with immune checkpoint inhibitors (ICIs) forefront, has revolutionized treatment. Nevertheless, tumor heterogeneity, evasion, presence immunosuppressive components within microenvironment (TIME) continue to compromise its efficacy. Furthermore, resistance or non-responsiveness ICIs some patients underscores urgent need unravel complexities TIME design innovative strategies that enhance immunotherapeutic outcomes. Emerging evidence revealed pivotal role N6-methyladenosine (m6A), prominent RNA methylation modification, shaping HCC. By regulating stability translation, m6A influences immune-related factors, including cytokines molecules. This modification governs PD-L1 expression, facilitating escape contributing against ICIs. Advances this field have also identified m6A-related regulators as promising biomarkers for predicting immunotherapy response potential targets optimizing treatment review examines regulatory mechanisms HCC, focus on impact cells cytokine dynamics. It explores targeting pathways improve efficacy outlines emerging directions future research. These insights aim provide foundation developing novel overcome advance

Language: Английский

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Nanozyme-Based Strategies in Cancer Immunotherapy: Overcoming Resistance to Enhance Therapeutic Efficacy

Aging and Disease, Journal Year: 2025, Volume and Issue: unknown, P. 0 - 0

Published: Jan. 1, 2025

Nanozymes, which are nanomaterials that replicate the catalytic activities of natural enzymes in biological systems, have recently demonstrated considerable potential improving cancer immunotherapy by altering tumor microenvironment. Nanozyme-driven immune responses represent an innovative therapeutic modality with high effectiveness and minimal side effects. These nanozymes activate system to specifically recognize destroy cells. Combined immunotherapeutic agents, can amplify anti-cancer integrating remodeling immunogenic cell death (ICD). This review offers a thorough discussion about various involved immunity, including those mimicking catalase (CAT), superoxide dismutase (SOD), peroxidase (POD), oxidase (OXD). It also discusses challenges future directions for translating nanozyme platforms into clinical applications, enhancing susceptibility cells immunotherapy. Nanozyme-based strategies substantial oncology, offering new effective options management.

Language: Английский

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Pharmacology of Epitranscriptomic Modifications: Decoding the Therapeutic Potential of RNA Modifications in Drug Resistance

European Journal of Pharmacology, Journal Year: 2025, Volume and Issue: 994, P. 177397 - 177397

Published: Feb. 18, 2025

Language: Английский

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RNA Modification in Metabolism

MedComm, Journal Year: 2025, Volume and Issue: 6(3)

Published: March 1, 2025

ABSTRACT Epigenetic regulation in disease development has been witnessed within this decade. RNA methylation is the predominant form of epigenetic regulation, and most prevalent modification N6‐methyladenosine (m 6 A). Recently, emerged as a potential target for treatment. posttranscriptional gene expression that involved both physiological pathological processes. Evidence suggests m A significantly affects metabolism, its abnormal changes have observed variety diseases. Metabolic diseases are series caused by metabolic processes body, common include diabetes mellitus, obesity, nonalcoholic fatty liver disease, etc.; although pathogenesis these differs from each other to current understanding, recent studies suggested pivotal role modulating diseases, A‐based drug on agenda. This paper reviewed understanding hoping provide systematic information those area.

Language: Английский

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m5C methylation of mitochondrial RNA and non-coding RNA by NSUN3 is associated with variant gene expression and asexual blood-stage development in Plasmodium falciparum

Parasites & Vectors, Journal Year: 2025, Volume and Issue: 18(1)

Published: March 27, 2025

Abstract Background Malaria is caused by Plasmodium spp. and a prevalent parasitic disease worldwide. To evade detection the immune system, switching variant gene expression, malaria parasite continually establishes new patterns displaying single erythrocyte surface antigen. The distinct molecules encoded clonally families include var , rif stevor Pfmc-2tm surfins . However, mechanism behind exclusive expression of member family still not clear. This study aims to describe molecular process from perspective epitranscriptome, specifically characterizing role falciparum RNA m5C methyltransferase NSUN3. Methods A conditional knockdown approach was adopted incorporating glucosamine-inducible glmS ribozyme sequence into 3′ untranslated region (UTR) pfnsun3 gene. transgenic line PfNSUN3-Ty1-Ribo generated using CRISPR-Cas9 methods. effect in measured growth curve assay western blot analysis. transcriptome changes influenced PfNUSN3 were detected sequencing (RNA-seq), direct transcripts regulated validated immunoprecipitation high-throughput (RIP-seq). Results Growth analysis revealed that PfNSUN3 interfered with growth. parasitemia showed significant decline at third round life cycle compared control line. altered global transcriptome. RNA-seq ring-stage depletion silenced almost all genes, as well guanine/cytosine (GC)-rich non-coding (ncRNA) ruf6 family. RIP-seq arrays directly interacted several genes. Conclusions Our findings demonstrate vital mutually contribute better understanding complex epigenetic regulation P. Graphical

Language: Английский

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Circular RNA in liver cancer research: biogenesis, functions, and roles

Frontiers in Oncology, Journal Year: 2025, Volume and Issue: 15

Published: March 28, 2025

Liver cancer, characterized by its insidious nature, aggressive invasiveness, and propensity for metastasis, has witnessed a sustained increase in both incidence mortality rates recent years, underscoring the urgent need innovative diagnostic therapeutic approaches. Emerging research indicates that CircRNAs (circular RNAs) are abundantly stably present within cells, with their expression levels closely associated progression of various malignancies, including hepatocellular carcinoma. In context liver cancer progression, circRNAs exhibit promising potential as highly sensitive biomarkers, offering novel avenues early detection, also function pivotal regulatory factors carcinogenic process. This study endeavors to elucidate biogenesis, functional roles, underlying mechanisms carcinoma, thereby providing fresh perspective on pathogenesis laying robust foundation development more precise effective tools strategies.

Language: Английский

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PCIF1 drives oesophageal squamous cell carcinoma progression via m6Am‐mediated suppression of MTF2 translation

Clinical and Translational Medicine, Journal Year: 2025, Volume and Issue: 15(4)

Published: March 28, 2025

Oesophageal squamous cell carcinoma (OSCC) represents a highly aggressive malignancy with limited therapeutic options and poor prognosis. This study uncovers PCIF1 as critical driver of OSCC progression via m6Am RNA modification, leading to translational repression the tumour suppressor MTF2. Our results demonstrate that selectively suppresses MTF2 translation, activating oncogenic pathways promote growth. In vitro in vivo models confirm knockdown reduces progression, whereas counteracts this effect, highlighting importance PCIF1-MTF2 axis. Clinical analyses further reveal high expression low correlate advanced stage, treatment response decreased overall survival. Furthermore, preclinical mouse model, knockout enhanced efficacy anti-PD1 immunotherapy, reducing burden improving histological outcomes. Notably, flow cytometry analysis indicated primarily exerts its effects through tumour-intrinsic mechanisms rather than direct modulation immune microenvironment, distinguishing mode action from PD1 blockade. These findings establish promising prognostic markers targets for OSCC, offering new avenues strategies patient stratification. KEY POINTS: promotes methylation at mRNA 5' cap. enhancing proliferation invasion. Targeting holds potential treatment.

Language: Английский

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5-Methylcytosine RNA modification and its roles in cancer and cancer chemotherapy resistance

Journal of Translational Medicine, Journal Year: 2025, Volume and Issue: 23(1)

Published: April 3, 2025

Recent advancements in cancer therapies have improved clinical outcomes, yet therapeutic resistance remains a significant challenge because of its complex mechanisms. Among epigenetic factors, m5C RNA modification is emerging as key player drug resistance, similar to the well-known m6A modification. affects metabolism processes, including splicing, export, translation, and stability, thereby influencing efficacy. This review highlights critical roles modulating chemotherapy, targeted therapy, radiotherapy, immunotherapy. also discusses functions regulators, methyltransferases, demethylases, m5C-binding proteins, essential modulators landscape that contribute dynamic regulatory network. Targeting these components offers promising strategy overcome resistance. We highlight need for further research elucidate specific mechanisms by which contributes develop precise m5C-targeted therapies, presenting m5C-focused strategies potential novel anticancer treatments.

Language: Английский

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