Methyltransferase-like 3 represents a prospective target for the diagnosis and treatment of kidney diseases

Abstract

Kidney disease is marked by complex pathological mechanisms and significant therapeutic hurdles, resulting in high morbidity and mortality rates globally. A deeper understanding of the fundamental processes involved can aid in identifying novel therapeutic targets and improving treatment efficacy. Current comprehensive data analyses indicate the involvement of methyltransferase-like 3 (METTL3) and its role in RNA N⁶-methyladenosine methylation in various renal pathologies, including acute kidney injury, renal fibrosis, and chronic kidney disease. However, there is a paucity of thorough reviews that clarify the functional mechanisms of METTL3 and evaluate its importance in enhancing therapeutic outcomes. This review seeks to systematically examine the roles, mechanisms, and potential clinical applications of METTL3 in renal diseases. The findings presented suggest that METTL3 is implicated in the etiology and exacerbation of kidney disorders, affecting their onset, progression, malignancy, and responsiveness to chemotherapeutic agents through the regulation of specific genetic pathways. In conclusion, this review underscores a detrimental correlation between METTL3 and kidney diseases, highlighting the therapeutic promise of targeting METTL3. Additionally, it offers critical insights for researchers concerning the diagnosis, prognosis, and treatment strategies for renal conditions.

Keywords: Acute kidney injury; Chronic kidney disease; Diagnosis; Methyltransferase-like 3; Pathogenesis; Renal fibrosis; Treatment.

Fig. 1

Cascades and mechanisms of METTL3 in different kidney diseases. The pathogenesis of AKI includes METTL3-induced mitochondrial impairment, inflammation, TEC apoptosis, and TEC ferroptosis. These events subsequently cause nephrotoxicity and extracellular matrix deposition around MECs, leading to renal parenchymal sclerosis and the formation of renal scar tissue, thereby inducing RF. The progression of RF is further marked by TEC senescence, dysfunction of both TECs and podocytes, as well as MEC proliferation and inflammation, ultimately resulting in CKD associated with obstructive nephropathy, diabetic nephropathy, or hypertensive nephropathy. Methyltransferase-like 3 (METTL3). N⁶-methyladenosine (m⁶A). Tubular epithelial cell (TEC). Mesangial cell (MEC). Insulin-like growth factor 2 mRNA binding protein family (IGF2BP). Forkhead box D1 (FOXD1). Kelch-like ECH-associated protein 1 (Keap1). Nuclear factor erythroid 2-related factor 2 (Nrf2). Transforming growth factor-β1 (TGF-β1). Connective tissue growth factor (CTGF). LncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). Focal adhesion kinase (FAK). YTH N⁶-methyladenosine RNA binding protein (YTHDF). Putative kinase 1 (PINK1). Nuclear receptor-binding SET domain protein 2 (NSD2). Tissue inhibitor of the metalloproteinase 2(TIMP2). NLR family pyrin domain-containing 3 (NLRP3). Tumor necrosis factor–α (TNF-α). Cellular MYC (c-MYC). Arginine vasopressin receptor 2 (Avpr2)