Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Дек. 10, 2023

Abstract Ferroptosis, a unique modality of cell death with mechanistic and morphological differences from other modes, plays pivotal role in regulating tumorigenesis offers new opportunity for modulating anticancer drug resistance. Aberrant epigenetic modifications posttranslational (PTMs) promote resistance, cancer progression, metastasis. Accumulating studies indicate that can transcriptionally translationally determine vulnerability to ferroptosis functions as driver nervous system diseases (NSDs), cardiovascular (CVDs), liver diseases, lung kidney diseases. In this review, we first summarize the core molecular mechanisms ferroptosis. Then, roles processes, including histone PTMs, DNA methylation, noncoding RNA regulation such phosphorylation, ubiquitination, SUMOylation, acetylation, ADP-ribosylation, are concisely discussed. The PTMs genesis cancers, NSD, CVDs, well application PTM modulators therapy these then discussed detail. Elucidating mediated by will facilitate development promising combination therapeutic regimens containing or PTM-targeting agents inducers be used overcome chemotherapeutic resistance could prevent addition, highlight potential approaches chemoresistance halt

Язык: Английский

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Epigenetics-targeted drugs: current paradigms and future challenges

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Ноя. 26, 2024

Epigenetics governs a chromatin state regulatory system through five key mechanisms: DNA modification, histone RNA remodeling, and non-coding regulation. These mechanisms their associated enzymes convey genetic information independently of base sequences, playing essential roles in organismal development homeostasis. Conversely, disruptions epigenetic landscapes critically influence the pathogenesis various human diseases. This understanding has laid robust theoretical groundwork for developing drugs that target epigenetics-modifying pathological conditions. Over past two decades, growing array small molecule targeting such as methyltransferase, deacetylase, isocitrate dehydrogenase, enhancer zeste homolog 2, have been thoroughly investigated implemented therapeutic options, particularly oncology. Additionally, numerous epigenetics-targeted are undergoing clinical trials, offering promising prospects benefits. review delineates epigenetics physiological contexts underscores pioneering studies on discovery implementation drugs. include inhibitors, agonists, degraders, multitarget agents, aiming to identify practical challenges avenues future research. Ultimately, this aims deepen epigenetics-oriented strategies further application settings.

Язык: Английский

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Writers, readers, and erasers RNA modifications and drug resistance in cancer

Molecular Cancer, Год журнала: 2024, Номер 23(1)

Опубликована: Авг. 30, 2024

Drug resistance in cancer cells significantly diminishes treatment efficacy, leading to recurrence and metastasis. A critical factor contributing this is the epigenetic alteration of gene expression via RNA modifications, such as N6-methyladenosine (m6A), N1-methyladenosine (m1A), 5-methylcytosine (m5C), 7-methylguanosine (m7G), pseudouridine (Ψ), adenosine-to-inosine (A-to-I) editing. These modifications are pivotal regulating splicing, translation, transport, degradation, stability. Governed by "writers," "readers," "erasers," impact numerous biological processes progression, including cell proliferation, stemness, autophagy, invasion, apoptosis. Aberrant can lead drug adverse outcomes various cancers. Thus, targeting modification regulators offers a promising strategy for overcoming enhancing efficacy. This review consolidates recent research on role prevalent resistance, with focus m6A, m1A, m5C, m7G, Ψ, A-to-I Additionally, it examines regulatory mechanisms linked underscores existing limitations field.

Язык: Английский

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Emerging Roles of RNA Methylation in Development

Accounts of Chemical Research, Год журнала: 2023, Номер 56(23), С. 3417 - 3427

Опубликована: Ноя. 15, 2023

More than 170 different types of chemical modifications have been identified on diverse RNA, collectively known as the epitranscriptome. Among them, N6-methyladenine (m6A), 5-methylcytosine (m5C), N1-methyladenine (m1A), and N7-methylguanosine (m7G) ubiquitous post-transcriptional modification are widely involved in regulating metabolic processes such RNA degradation, translation, stability, export, mediating important physiological pathological stress regulation, immune response, development, tumorigenesis. Recently, regulatory role during developmental is getting more attention. Therefore, development low-input even single-cell high-resolution sequencing technologies crucial for exploration roles these biological events trace samples.This account focuses various processes. We describe distribution characteristics modifications, catalytic enzymes, binding proteins, technologies. dynamically reversible, which can be catalyzed by methyltransferases eliminated demethylases. m6A most abundant eukaryote mRNA, mainly concentrated near stop codon, involves metabolism regulation. m5C, another studied modification, has a organisms species, enriched regions downstream translation initiation sites broadly distributes across whole coding sequence (CDS) mammalian mRNAs. m1A, with lower abundance m6A, distributed types, locates 5' untranslated region (5'UTR) mRNA regulates translation. m7G, one common eukaryotes, at cap internal positions RNAs recently gained considerable attention.Thanks to technology, found regulate tumorigenic process, including tumor proliferation, invasion, metastasis modulating oncogenes suppressor genes, affect oocyte maturation embryonic through maternal zygotic genes. m5C related proteins participate plant growth, neural stem cell differentiation dependent manner. m1A also revealed m7G dysregulation neurodevelopmental disorders neurodegenerative diseases.Collectively, we summarized gradually exhibited methylation discussed possibility candidate biomarkers potential therapeutic targets. The technological anticipated major driving force expand our knowledge this field.

Язык: Английский

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Targeting methionine metabolism in cancer: opportunities and challenges

Trends in Pharmacological Sciences, Год журнала: 2024, Номер 45(5), С. 395 - 405

Опубликована: Апрель 5, 2024

Язык: Английский

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Epigenetic modification of ferroptosis by non-coding RNAs in cancer drug resistance

Molecular Cancer, Год журнала: 2024, Номер 23(1)

Опубликована: Авг. 27, 2024

Abstract The development of drug resistance remains a major challenge in cancer treatment. Ferroptosis, unique type regulated cell death, plays pivotal role inhibiting tumour growth, presenting new opportunities treating chemotherapeutic resistance. Accumulating studies indicate that epigenetic modifications by non-coding RNAs (ncRNA) can determine vulnerability to ferroptosis. In this review, we first summarize the growth/development. Then, core molecular mechanisms ferroptosis, its upstream regulation, and downstream effects on Finally, review recent advances understanding how ncRNAs regulate ferroptosis from such modulate This aims enhance general ncRNA-mediated regulatory which highlighting ncRNA-ferroptosis axis as key druggable target overcoming

Язык: Английский

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The m7G Methyltransferase Mettl1 Drives Cardiac Hypertrophy by Regulating SRSF9‐Mediated Splicing of NFATc4

Advanced Science, Год журнала: 2024, Номер 11(29)

Опубликована: Май 29, 2024

Cardiac hypertrophy is a key factor driving heart failure (HF), yet its pathogenesis remains incompletely elucidated. Mettl1-catalyzed RNA N7-methylguanosine (m7G) modification has been implicated in ischemic cardiac injury and fibrosis. This study aims to elucidate the role of Mettl1 mechanism underlying non-ischemic HF. It found that upregulated human failing hearts hypertrophic murine following transverse aortic constriction (TAC) Angiotensin II (Ang II) infusion. YY1 acts as transcriptional for during hypertrophy. knockout alleviates dysfunction upon pressure overload from TAC or Ang stimulation. Conversely, cardiac-specific overexpression results remodeling. Mechanically, increases SRSF9 expression by inducing m7G mRNA, facilitating alternative splicing stabilization NFATc4, thereby promoting Moreover, knockdown protects against TAC- Mettl1-induced phenotypes vivo vitro. The identifies crucial regulator hypertrophy, providing novel therapeutic target

Язык: Английский

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FSH induces EMT in ovarian cancer via ALKBH5-regulated Snail m6A demethylation

Theranostics, Год журнала: 2024, Номер 14(5), С. 2151 - 2166

Опубликована: Янв. 1, 2024

Background:The therapeutic benefits of targeting follicle-stimulating hormone (FSH) receptor in treatment ovarian cancer are significant, whereas the role FSH progresses and underlying mechanism remains to be developed.Methods: Tissue microarray human cancer, tumor xenograft mouse model, vitro cell culture were used investigate carcinogenesis.siRNA, lentivirus inhibitors trigger inactivation genes, plasmids increase transcription genes.Specifically, pathological characteristic was assessed by histology immunohistochemistry (IHC), while signaling pathway studied using western blot, quantitative RT-PCR, immunofluorescence.Results: Histology IHC normal tissue confirmed association between Snail metastasis.Moreover, epithelial cells mice, showed promote mesenchymal transition (EMT) progress metastasis via prolonging half-life mRNA a N6-methyladenine methylation (m6A) dependent manner, which mechanistically through CREB/ALKBH5 pathway.Conclusions: These findings indicated that induces EMT progression CREB/ALKBH5/Snail pathway.Thus, this study provided new insight into strategy patients with high level FSH.

Язык: Английский

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ALKBH5 suppresses gastric cancer tumorigenesis and metastasis by inhibiting the translation of uncapped WRAP53 RNA isoforms in an m6A-dependent manner

Molecular Cancer, Год журнала: 2025, Номер 24(1)

Опубликована: Янв. 15, 2025

The N6-methyladenosine (m6A) modification serves as an essential epigenetic regulator in eukaryotic cells, playing a significant role tumorigenesis and cancer progression. However, the detailed biological functions underlying mechanisms of m6A regulation gastric (GC) are poorly understood. Our research revealed that demethylase ALKBH5 was markedly downregulated GC tissues, which associated with poor patient prognosis. Functional studies demonstrated suppressing expression enhanced cell proliferation, migration, invasion. Mechanistically, removed modifications from 5' uncapped polyadenylated transcripts (UPTs) WRAP53. This demethylation decreased WRAP53 stability translation efficiency. lower level disrupts interaction between USP6 RALBP1 protein, promoting degradation thereby PI3K/Akt/mTOR signaling cascade, ultimately attenuating progression GC. These findings highlight pivotal ALKBH5-mediated inhibiting potential promising biomarker therapeutic target for intervention.

Язык: Английский

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Insight into the roles of lactylation in macrophages: functions and clinical implications

Clinical Science, Год журнала: 2025, Номер 139(02), С. 151 - 169

Опубликована: Янв. 1, 2025

Lactylation, a post-translational modification, has been linked to gene transcription regulation through epigenetic modulation in various pathophysiological processes. The lactylation regulatory proteins, known as writers, erasers, and readers, govern their dynamics by adding, removing, recognizing lactyl groups on proteins. Macrophages, cells of the immune system, maintain homeostasis, responding dynamically diverse internal external stimuli. Emerging researches unveil that lactylation, inducing macrophage activation polarization, affects functionality pathological conditions such inflammation, tumor microenvironment, fibrosis. Evidence progressively indicates lactate-driven alterations levels within macrophages can influence pathogenesis numerous diseases. This review aims systematically summarize research progress macrophages, explore its functions mechanisms which contributes pathology different disease phenotypes, propose future directions along with potential diagnostic therapeutic strategies.

Язык: Английский

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