RNA methylation in kidney disorders: Insights into molecular machinery and therapeutic opportunities

Kidney disorders, including acute kidney injury (AKI), chronic kidney disease (CKD), diabetic nephropathy (DN), and clear cell renal cell carcinoma (ccRCC), represent major causes of morbidity and mortality worldwide and remain significant challenges in clinical management because of their complex pathogenesis and limited therapeutic options. Recent advances in epitranscriptomics have highlighted RNA methylation as an important post-transcriptional regulatory mechanism involved in renal physiology and disease development. Diverse RNA modifications, including N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), N7-methylguanosine (m7G), and 3-methylcytidine (m3C), dynamically regulate RNA metabolism by affecting transcript stability, translation, splicing, and degradation. Increasing evidence demonstrates that RNA methylation regulators, including methyltransferases such as METTL3 and METTL14, demethylases such as FTO and ALKBH5, and reader proteins such as YTH domain-containing family members, participate in multiple pathogenic processes, including inflammation, fibrosis, oxidative stress, metabolic dysregulation, and tumor progression in renal disorders. Aberrant expression of these regulators has been closely associated with disease severity and progression. In this review, we summarize current knowledge regarding major RNA methylation modifications and their regulatory machinery in a spectrum of kidney diseases, with particular emphasis on the molecular mechanisms through which RNA methylation influences renal injury and repair. We further discuss the emerging value of RNA methylation-related molecules as potential biomarkers and therapeutic targets, aiming to provide new insights into epitranscriptomic regulation in kidney disease and its translational potential.