Author: Zhou, Xinyi ; Lin, Weimin ; Yuan, Quan ; Huang, Shenzhen ; Seriwatanachai, Dutmanee ; Shao, Bin ; Qi, Xingying ; Yang, Xiaoyu ; Lin, Guifeng ; Yang, Shengyong ; Li, Hanwen ; Lei, Kexin ; Wang, Qian

AbstractN6‐methyladenosine (m6A) modification, installed by METTL3‐METTL14 complex, is abundant and critical in eukaryotic mRNA. However, its role in oral mucosal immunity remains ambiguous. Periodontitis is a special but prevalent infectious disease characterized as hyperinflammation of oral mucosa and bone resorption. Here, it is reported that genetic deletion of Mettl3 alleviates periodontal destruction via suppressing NLRP3 inflammasome activation. Mechanistically, the stability of TNFAIP3 (also known as A20) transcript is significantly attenuated upon m6A modification. When silencing METTL3, accumulated TNFAIP3 functioning as a ubiquitin‐editing enzyme facilitates the ubiquitination of NEK7 [NIMA (never in mitosis gene a)‐related kinase 7], and subsequently impairs NLRP3 inflammasome assembly. Furtherly, Coptisine chloride, a natural small‐molecule, is discovered as a novel METTL3 inhibitor and performs therapeutic effect on periodontitis. The study unveils a previously unknown pathogenic mechanism of METTL3‐mediated m6A modifications in periodontitis and indicates METTL3 as a potential therapeutic target.

Inflammation

Melatonin via MTNR1B regulates METTL3 to protect ileum cell differentiation

Article

Author: Chen, Yaoxing ; Li, Yuanyuan ; Sun, Yan ; Dong, Yulan

Intestinal stem cells rapidly differentiate into various epithelial cells, playing a crucial role in maintaining intestinal homeostasis. Melatonin, a known endogenous molecule with anti-inflammatory and antioxidant properties, has its potential efficacy in ileum stem cells differentiation not fully understood to date. This study indicates that melatonin suppresses ileum inflammation and maintains normal differentiation of ileum stem cells through MTNR1B. Subsequent outcomes following treatment with MTNR1B inhibitors further substantiate these findings. Additionally, overexpression of METTL3 protein appears to be a potential instigator for promoting ileum inflammation and disruptions in cell differentiation. Treatment with the METTL3 inhibitor SAH significantly inhibits ileum inflammation and Wnt/β-catenin activity, thereby sustaining normal cellular differentiation functions. In summary, this study showed that melatonin may improve ileum inflammation and maintain cell differentiation functions by inhibiting abnormal METTL3 expression via MTNR1B.

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Myeloid Leukemia	Preclinical	US	Accent Therapeutics, Inc.Startup	22 Aug 2023
Acute Myeloid Leukemia	Preclinical	FR	Ipsen SA	22 Aug 2023

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