{"doi":"10.1002/ctd2.246","title":"Understanding the interplay between N6‐methyladenine RNA methylation and noncoding RNAs in kidney disease","abstract":"First discovered in 1974,1 N6-methyladenosine (m6A) is the most prevalent epigenetic modification in eukaryotic mRNAs at the posttranscriptional level under pathophysiological conditions. The m6A modification entails methylation of adenine at the nitrogen 6 (N6) position. Three classes of enzymes mediate the process of m6A modification, including RNA methyltransferases (writers), demethylases (erasers), and methylation recognition proteins (readers).2 Writers can form a multicomponent m6A methyltransferase complex (MTC) that catalyzes RNA modification by transferring methyl groups to RNA. In MTC, METTL3, METTL14 and WTAP are core components. Serving as erasers, as the name implies, demethylases (FTO and ALKBH5) are responsible for removing S-adenosyl methionine from adenines in RNA. At the same time, readers (YTHDF, YTHDC and eIF3) can recognize m6A-modified RNAs and bind the m6A modification, subsequently determining the fate of the RNA. Therefore, m6A RNA modification is considered invertible and dynamic. In recent years, the advent of advanced high-throughput sequencing has facilitated the identification of m6A. In general, m6A presents 0.4%−0.6% of all cellular RNAs, including mRNAs, noncoding RNAs (ncRNAs), and circular RNAs (circRNAs).3 In a recent publication in Clinical and Translational Medicine, Ni et al. reported that METTL3 promoted the m6A modification of Ena/VASP-like (EVL) mRNA and subsequently activated the transforming growth factor-beta 1 (TGF-β1) signalling pathway, which ultimately aggravated kidney fibrosis.4 Beyond regulating mRNA-coding genes, m6A modification exhibited remarkable capacity in modulating the function of ncRNAs to dictate kidney fate after various insults, especially in kidney carcinoma. Conversely, ncRNAs also participate in the regulation of m6A modification amid kidney disease progression. Therefore, fully understanding the crosstalk between m6A modification and ncRNAs will supplement a piece of the puzzle of the pathogenesis of non-tumour kidney diseases and shed light on developing effective therapeutic strategies for these medical catastrophes. ncRNAs, mainly comprised of micro RNAs (miRNAs), long noncoding RNAs (lncRNAs), and circRNAs, account for a large class of transcripts in mammalian genomes without protein-coding potential. Despite this, they are crucial regulators of diverse physiological and pathological processes. The m6A modification of ncRNAs controls RNA stability, processing, and transport. As illustrated in Figure 1, accumulating studies have shown that m6A-modified ncRNAs cause kidney disorders through multiple dysregulated signalling pathways in diseased kidneys. Because the evidence of m6A modification of circRNAs remains lacking, we mainly focus on introducing the role of miRNAs and lncRNAs in the kidney system. miRNAs make up the majority of ncRNAs, and the role of m6A modification of miRNA is complex and diverse. For instance, in vitro, METTL3 positively modulated miR-873-5p to attenuate oxidative stress and apoptosis by regulating the Keap1/Nrf2 pathway in the cultured proximal tubular cells stimulated with colistin.5 In vivo, METTL3-mediated m6A modification promoted miR-21-5p maturation. Matured miR-21-5p subsequently activated the SPRY1/ERK/NF-κB axis in the obstructive kidneys, exacerbating inflammation and ultimately driving kidney fibrosis.6 As depicted in these findings, m6A modification may exert opposite regulatory roles at different stages of miRNA maturation. Therefore, obtaining a full image of m6A modification of miRNA is required to elucidate the regulatory mechanisms in-depth and their impact on the development of kidney disease. In comparison, lncRNA was found to regulate gene expression via interacting with RNA molecules, modulating protein post-translational modifications, or remodelling chromatin states despite lacking an open reading framework. m6A modification participates in lncRNA biogenesis and regulates numerous kidney cell activities. I","journal":"Clinical and Translational Discovery","year":2023,"id":412049,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9511,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":366339,"name":"Dong Zhou","orcid":"0000-0003-1981-8745","position":1,"is_corresponding":false},{"id":1192977,"name":"Saiya Zhu","orcid":null,"position":0,"is_corresponding":true}],"reference_count":13,"raw_metadata":null,"created_at":"2026-07-19T01:21:46.548301Z","pmid":"41180424","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}