METTL3 Potentiates M2 Macrophage‐Driven MMT to Aggravate Renal Allograft Fibrosis via the TGF‐β1/Smad3 Pathway DOI Creative Commons

Qinfan Yao,

Xiaoxiao Zheng, Xinyi Zhang

et al.

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 27, 2025

Abstract METTL3, a key enzyme in N6‐methyladenosine (m6A) modification, plays crucial role the progression of renal fibrosis, particularly chronic active allograft rejection (CAR). This study explored mechanisms by which METTL3 promotes focusing on its macrophage‐to‐myofibroblast transition (MMT). Using comprehensive experimental approach, including TGF‐β1‐induced MMT cell models, conditional knockout (METTL3 KO) mice, and biopsy samples from patients with CAR, investigates involvement METTL3/Smad3 axis driving fibrosis during episodes CAR. We found that elevated m6A modification levels strongly correlated enhanced increased fibrotic severity. significantly Smad3, decreased Smad3 expression, inhibited M2‐driven MMT. knockdown siRNA (siSmad3) further MMT, while overexpression rescued inhibitory effects silencing, restoring tissue damage. Additionally, inhibitor STM2457 effectively reversed alleviated damage These findings highlight enhances CAR promoting TGF‐β1/Smad3 axis, suggesting is promising therapeutic target for mitigating

Language: Английский

Cisplatin nephrotoxicity: new insights and therapeutic implications DOI
Chengyuan Tang, Man J. Livingston,

Robert L. Safirstein

et al.

Nature Reviews Nephrology, Journal Year: 2022, Volume and Issue: 19(1), P. 53 - 72

Published: Oct. 13, 2022

Language: Английский

Citations

266
Inhibition of ALKBH5 attenuates I/R-induced renal injury in male mice by promoting Ccl28 m6A modification and increasing Treg recruitment DOI Creative Commons
Juntao Chen,

Cuidi Xu,

Kun Yang

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: March 1, 2023

Abstract Ischemia reperfusion injury (IRI) is a common cause of acute kidney (AKI). The role N 6- methyladenosine (m6A) modification in AKI remains unclear. Here, we characterize the AlkB homolog 5 (ALKBH5) and m6A an I/R-induced renal model male mice. Alkbh5 -knockout mice exhibit milder pathological damage better function than wild-type post-IRI, whereas -knockin show contrary results. Also conditional knockout tubular epithelial cells alleviates fibrosis. CCL28 identified as target ALKBH5. Furthermore, Ccl28 mRNA stability increases with deficiency, mediating by binding insulin-like growth factor 2 protein 2. Treg recruitment upregulated inflammatory are inhibited increased level IRI- fl/fl Ksp Cre ALKBH5 inhibitor IOX1 exhibits protective effects against AKI. In summary, inhibition promotes modifications Ccl 28 mRNA, enhancing its stability, regulating Treg/inflammatory cell axis. this axis potential treatment target.

Language: Английский

Citations

73
STING/ACSL4 axis-dependent ferroptosis and inflammation promote hypertension-associated chronic kidney disease DOI Creative Commons
Li Gao, Jun‐Sheng Zhang, Tingting Yang

et al.

Molecular Therapy, Journal Year: 2023, Volume and Issue: 31(10), P. 3084 - 3103

Published: Aug. 2, 2023

Hypertension is a primary modifiable risk factor for cardiovascular diseases, which often induces renal end-organ damage and complicates chronic kidney disease (CKD). In the present study, histological analysis of human samples revealed that hypertension induced mtDNA leakage promoted expression stimulator interferon genes (STING) in epithelial cells. We used angiotensin II (AngII)- 2K1C-treated mouse kidneys to elucidate underlying mechanisms. Abnormal packing caused by AngII STING-dependent production inflammatory cytokines, macrophage infiltration, fibrogenic response. STING knockout significantly decreased nuclear factor-κB activation immune cell attenuating tubule atrophy extracellular matrix accumulation vivo vitro. These effects delayed CKD progression. Immunoprecipitation assays liquid chromatography-tandem mass spectrometry showed ACSL4 were directly combined at D53 K412 amino acids ACSL4. Furthermore, response fibrosis through ACSL4-dependent ferroptosis. Last, inhibition using small interfering RNA, rosiglitazone, or Fer-1 downregulated AngII-induced mtDNA-STING-dependent inflammation. results suggest targeting STING/ACSL4 axis might represent potential strategy treating hypertension-associated CKD.

Language: Английский

Citations

49
Chemically Modified Platforms for Better RNA Therapeutics DOI

Yesi Shi,

Xueyan Zhen,

Yiming Zhang

et al.

Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(3), P. 929 - 1033

Published: Jan. 29, 2024

RNA-based therapies have catalyzed a revolutionary transformation in the biomedical landscape, offering unprecedented potential disease prevention and treatment. However, despite their remarkable achievements, these encounter substantial challenges including low stability, susceptibility to degradation by nucleases, prominent negative charge, thereby hindering further development. Chemically modified platforms emerged as strategic innovation, focusing on precise alterations either RNA moieties or associated delivery vectors. This comprehensive review delves into platforms, underscoring significance augmenting performance translational prospects of therapeutics. It encompasses an in-depth analysis various chemically that been instrumental propelling therapeutics toward clinical utility. Moreover, scrutinizes rationale behind diverse chemical modification techniques aiming at optimizing therapeutic efficacy molecules, facilitating robust management. Recent empirical studies corroborating enhancement through modifications are highlighted. Conclusively, we offer profound insights transformative impact drugs delineates prospective trajectories for future development integration.

Language: Английский

Citations

46
Histone lactylation-regulated METTL3 promotes ferroptosis via m6A-modification on ACSL4 in sepsis-associated lung injury DOI Creative Commons
Dan Wu,

Charles B. Spencer,

Lilibeth Ortoga

et al.

Redox Biology, Journal Year: 2024, Volume and Issue: 74, P. 103194 - 103194

Published: May 16, 2024

Elevated lactate levels are a significant biomarker of sepsis and positively associated with sepsis-related mortality. Sepsis-associated lung injury (ALI) is leading cause poor prognosis in clinical patients. However, the underlying mechanisms lactate's involvement sepsis-associated ALI remain unclear. In this study, we demonstrate that regulates N6-methyladenosine (m6A) modification by facilitating p300-mediated H3K18la binding to METTL3 promoter site. The METTL3-mediated m6A enriched ACSL4, its mRNA stability regulated through YTHDC1-dependent pathway. Furthermore, short-term stimulation upregulates which promotes mitochondria-associated ferroptosis. Inhibition knockdown or targeted inhibition effectively suppresses septic hyper-lactate-induced ferroptosis alveolar epithelial cells mitigates mice. Our findings suggest induces via GPR81/H3K18la/METTL3/ACSL4 axis during ALI. These results reveal histone lactylation-driven mechanism inducing modification. Targeting represents promising therapeutic strategy for patients

Language: Английский

Citations

38
Epigenetics-targeted drugs: current paradigms and future challenges DOI Creative Commons

Wanlin Dai,

Xinbo Qiao, Yuanyuan Fang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Nov. 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.

Language: Английский

Citations

28
Inhibition of METTL3 ameliorates doxorubicin-induced cardiotoxicity through suppression of TFRC-mediated ferroptosis DOI Creative Commons
Lin Wu, Yuxin Du, Litao Wang

et al.

Redox Biology, Journal Year: 2024, Volume and Issue: 72, P. 103157 - 103157

Published: April 12, 2024

Doxorubicin (DOX) is a chemotherapeutic drug, while its clinical use greatly limited by the life-threatening cardiotoxicity. N6-methyladenosine (m6A) RNA modification participates in varieties of cellular processes. Nonetheless, it remains elusive whether m6A and methyltransferase METTL3 are involved progression DOX-induced cardiotoxicity (DIC). Mice were administrated with DOX (accumulative dosage 20 mg/kg) repeatedly to establish chronic DIC model. Cardiomyocyte-specific conditional knockout mice employed evaluate effects altered on DIC. The cardiomyocyte ferroptosis also examined response stimulation. led increased levels expression cardiomyocytes c-Jun-dependent manner. METTL3-knockout exhibited improved cardiac function, remodeling injury following insult. Besides, inhibition alleviated iron accumulation cardiomyocytes, whereas overexpression exerted opposite effects. Mechanistically, promoted TFRC mRNA, critical gene governing uptake, enhanced stability through recognition reader protein, IGF2BP2. Moreover, pharmacological administration highly selective inhibitor STM2457 effectively ameliorated mice. plays cardinal role etiology regulating metabolism modification. Inhibition might be potential therapeutic avenue for

Language: Английский

Citations

21
Inhibition of METTL3 Alleviates NLRP3 Inflammasome Activation via Increasing Ubiquitination of NEK7 DOI Creative Commons
Xinyi Zhou, Xiaoyu Yang,

Shenzhen Huang

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: 11(26)

Published: May 2, 2024

Abstract N6‐methyladenosine (m 6 A) modification, installed by METTL3‐METTL14 complex, is abundant and critical in eukaryotic mRNA. However, its role oral mucosal immunity remains ambiguous. Periodontitis a special but prevalent infectious disease characterized as hyperinflammation of mucosa bone resorption. Here, it reported that genetic deletion Mettl3 alleviates periodontal destruction via suppressing NLRP3 inflammasome activation. Mechanistically, the stability TNFAIP3 (also known A20) transcript significantly attenuated upon m A modification. When silencing METTL3, accumulated functioning ubiquitin‐editing enzyme facilitates ubiquitination NEK7 [NIMA (never mitosis gene a)‐related kinase 7], subsequently impairs assembly. Furtherly, Coptisine chloride, natural small‐molecule, discovered novel METTL3 inhibitor performs therapeutic effect on periodontitis. The study unveils previously unknown pathogenic mechanism METTL3‐mediated modifications periodontitis indicates potential target.

Language: Английский

Citations

19
METTL3: a multifunctional regulator in diseases DOI
Na Li, Wei Xiang,

J.J. Dai

et al.

Molecular and Cellular Biochemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 24, 2025

Language: Английский

Citations

2
Crosstalk among m6A RNA methylation, hypoxia and metabolic reprogramming in TME: from immunosuppressive microenvironment to clinical application DOI Creative Commons
Fusheng Zhang, Haiyang Liu,

Meiqi Duan

et al.

Journal of Hematology & Oncology, Journal Year: 2022, Volume and Issue: 15(1)

Published: July 6, 2022

Abstract The tumor microenvironment (TME), which is regulated by intrinsic oncogenic mechanisms and epigenetic modifications, has become a research hotspot in recent years. Characteristic features of TME include hypoxia, metabolic dysregulation, immunosuppression. One the most common RNA N6-methyladenosine (m 6 A) methylation, widely involved regulation physiological pathological processes, including development. Compelling evidence indicates that m A methylation regulates transcription protein expression through shearing, export, translation, processing, thereby participating dynamic evolution TME. Specifically, methylation-mediated adaptation to phenotypic shift immune cells synergistically promote formation an immunosuppressive supports proliferation metastasis. In this review, we have focused on involvement tumor-adaptive described detailed linking change cell biological functions. view collective data, advocate treating as complete ecosystem components crosstalk with each other achieve adaptive changes. Finally, describe potential utility methylation-targeted therapies immunotherapy clinical applications challenges faced, aim advancing research.

Language: Английский

Citations

60