METTL1-mediated N7-methylguanosine epitranscriptomic alterations modulate mRNA stability of neurodegenerative disease-associated genes following cobalt exposure.

METTL1/WDR4 Complex: A Novel Epitranscriptomic Target at the Crossroads of RNA Methylation and Drug Discovery

Advances provide the first chemical foothold for therapeutic modulation of m7G pathways and underscore METTL1 as a promising yet complex target requiring careful biological stratification.

Identification of SLC2A3 as a Downstream Target of METTL1- mediated N7-methylguanosine Modification During MNNG-induced Gastric Carcinogenesis.

INTRODUCTION Methyl-N'-nitro-N-nitrosoguanidine (MNNG) is an environmental carcinogen that induces Gastric Cancer (GC). N7-methylguanosine (m7G) is a prevalent RNA modification closely linked to cancer onset and progression. However, the role of m7G in regulating gene expression during MNNG-induced gastric carcinogenesis remains unclear. This study aims to investigate the role of m7G modification in MNNG-induced GC and to identify potential downstream regulatory genes. METHODS Cell proliferation and migration were evaluated using CCK-8 and scratch assays in Malignant transformed cells (MC) and GC cells with different METTL1 expression levels. The m7G MeRIP-seq and whole-transcriptome sequencing were integrated to screen potential genes regulated by m7G modification in MC-30 cells. GO and KEGG analyses were performed for gene function. Candidate gene expression was screened and validated in MC and GC cells by RT-qPCR. Finally, we validated SLC2A3 by analyzing gene expression using the TCGA STAD cohort and 24 pairs of clinical GC samples. RESULTS METTL1 knockdown significantly inhibited proliferation and migration by about 25% (p < 0.001). Sequencing analysis identified SLC2A3 as a key METTL1 downstream target, with significantly altered m7G modification levels (fold change > 2, p < 0.05) and enrichment in cancer-related pathways. Clinically, SLC2A3 expression was significantly up-regulated in GC tissues versus normal controls (FC = 2.52, p < 0.001) and was significantly associated with tumor stage and prognosis in GC patients (p < 0.05). CONCLUSION Our study revealed that m7G methyltransferase METTL1 plays an oncogenic role in MNNG-induced gastric carcinogenesis. SLC2A3 is a key downstream target of METTL1, which is associated with clinical progression in GC patients. These findings may provide evidence for developing prognostic biomarkers for GC.

ZCCHC4-mediated m6A methylation regulates the UHRF1/CDO1 axis to inhibit ferroptosis and promote osteosarcoma malignant progression.

BACKGROUND Osteosarcoma (OS) represents a common primary malignant bone tumor associated with unfavorable clinical outcomes. Growing evidence underscores the crucial involvement of N6-methyladenosine (m6A) modifications in tumor development, but the specific mechanisms underlying the m6A regulatory network in OS remain to be elucidated. METHODS Potential key target genes in OS were identified through bioinformatic analyses, followed by the characterization of m6A-related regulatory proteins, specifically, writer and reader proteins, which showed significant associations with these targets. To elucidate the mechanistic role of m6A methylation in regulating UHRF1 expression, a series of in vitro assays were conducted. These included RNA pull-down, MeRIP-PCR, dot blot, dual-luciferase reporter assays, and RNA stability assays, which collectively confirmed the interaction between m6A regulatory proteins and UHRF1 mRNA. For functional investigations, OS cell lines (U2OS, Saos2, and 143B) with gene silencing or overexpression were established, and the role of UHRF1 in cellular proliferation, migration, and invasion was assessed using CCK-8 assays, Transwell migration and invasion assays, flow cytometry, and wound healing assays. In addition, GSH/GSSG ratio, Fe2+ concentration, and ROS levels were measured using commercial assay kits to explore ferroptosis-related functional mechanisms. To validate the in vivo relevance of our findings, a xenograft mouse model was established. Finally, functional rescue experiments were performed to mechanistically confirm the critical role of the ZCCHC4-UHRF1-CDO1 regulatory axis in OS progression. RESULTS ZCCHC4, functioning as an m6A methyltransferase, enhances the stability of UHRF1 mRNA by catalyzing its m6A modification, thereby promoting increased expression of UHRF1. In parallel, IGF2BP3, an established m6A reader protein, specifically recognizes and binds to the m6A-modified sites on UHRF1 mRNA, further stabilizing the transcript and modulating its downstream biological functions. METTL3/METTL14 knockdown experiments ruled out the contribution of classical m6A methyltransferases, confirming that ZCCHC4 is the primary methyltransferase for UHRF1. Dual-luciferase assays and bisulfite sequencing revealed that UHRF1 suppresses CDO1 transcription by inducing high methylation of its promoter, thereby reducing ROS/Fe2+ levels and increasing GSH, which in turn blocks ferroptosis. In U2OS, Saos2, and 143B cells, silencing UHRF1 or ZCCHC4 inhibited proliferation, migration, and invasion while activating ferroptosis. Overexpression of UHRF1 had the opposite effect. In vivo models confirmed that UHRF1 silencing inhibited tumor growth. Furthermore, UHRF1 overexpression partially reversed the phenotypes induced by ZCCHC4 knockdown. CONCLUSION In summary, this study reveals for the first time the complete molecular mechanism by which ZCCHC4-mediated UHRF1 m6A methylation promotes OS progression through epigenetic suppression of CDO1 transcription and inhibition of ferroptosis. This regulatory axis (ZCCHC4-IGF2BP3-UHRF1-CDO1-ferroptosis) provides multiple therapeutic targets for OS and lays a solid foundation for the future development of anticancer strategies based on the regulation of ferroptosis, while also offering a promising pathway for clinical translation.

Cortical organoids reveal human-specific role of METTL5 in neurodevelopment via regulation of CHCHD2.

Overexpression of CHCHD2 in METTL5-KO NPCs rescued proliferation and partially rescued oxidative metabolism in NPCs and ventricle formation in organoids, highlighting a previously uncharacterized connection between CHCHD2, oxidative metabolism, and METTL5-mediated regulation of human neurogenesis.

The m6A Reader YTHDC2: Molecular Mechanisms and Regulatory Networks in Disease Pathogenesis

This review systematically synthesizes current knowledge regarding the multifaceted roles of YTHDC2 in disease progression, prognosis, and therapy, offering a comprehensive framework to guide future investigations.

METTL3–YTHDF1–driven m6A enhancement of MYC signaling orchestrates DNA repair and metabolic reprogramming to promote chemoresistance in colorectal cancer