RNA N⁶‐methyladenosine modifications and potential targeted therapeutic strategies in kidney disease

Abstract

Epigenetic modifications have received increasing attention and have been shown to be extensively involved in kidney development and disease progression. Among them, the most common RNA modification, N6‐methyladenosine (m6A), has been shown to dynamically and reversibly exert its functions in multiple ways, including splicing, export, decay and translation initiation efficiency to regulate mRNA fate. Moreover, m6A has also been reported to exert biological effects by destabilizing base pairing to modulate various functions of RNAs. Most importantly, an increasing number of kidney diseases, such as renal cell carcinoma, acute kidney injury and chronic kidney disease, have been found to be associated with aberrant m6A patterns. In this review, we comprehensively review the critical roles of m6A in kidney diseases and discuss the possibilities and relevance of m6A‐targeted epigenetic therapy, with an integrated comprehensive description of the detailed alterations in specific loci that contribute to cellular processes that are associated with kidney diseases.

Genetic and pharmacological inhibition of METTL3 alleviates renal fibrosis by reducing EVL m6A modification through an IGF2BP2‐dependent mechanism

“…Although the potent functions of METTL3 have attracted increasing attention, the exploration of disease therapies targeting METTL3 is still in its infancy. 41,42 One study revealed that inhibition of METTL3 by the small molecule compound STM2457 is a promising therapeutic strategy for acute myeloid leukemia. 22 Additionally, inhibition of METTL3 by the small molecule compound Cpd-564 significantly reduces renal inflammation, providing a potential therapeutic strategy for AKI.…”

“…Functional and mechanistic exploration serves as the solid foundation for interventional therapeutic studies of diseases. Although the potent functions of METTL3 have attracted increasing attention, the exploration of disease therapies targeting METTL3 is still in its infancy 41,42 . One study revealed that inhibition of METTL3 by the small molecule compound STM2457 is a promising therapeutic strategy for acute myeloid leukemia 22 .…”

Shining a spotlight on m6A and the vital role of RNA modification in endometrial cancer: a review

“…The disruption of gene expression patterns controlled by epigenetics can lead to autoimmune diseases, infection, cancers ( Wang et al, 2022 ), inflammatory, autoimmune diseases and a variety of other diseases ( Cui et al, 2022 )and m6A methylation plays an important role in both hypertrophic and ischemic heart disease ( Kumari et al, 2022 ), kidney diseases ( Ni et al, 2023 ), such as renal cell carcinoma, acute kidney injury and chronic kidney disease, osteosarcoma ( Wu et al, 2022 ) and other different types of cancers. In a variety of cancers, m6A was found to play different roles, the same regulator has different functions in different cancers, and even different cell lines of the same cancer, and the phenotypes of regulator interventions with similar functions in the same cancer are also different.…”

N6-methyladenosine methylation in kidney injury

“…Wang, Wang [ 185 ] found that genetic and pharmacological inhibition of METTL3 can significantly reduce renal inflammatory injury and is a potential treatment for AKI. The small molecule compound Cpd564 was virtually screened by high-throughput sequencing and further validated to bind and inhibit METTL3 activity, which could further attenuate renal inflammatory injury [ 186 ]. The anticancer effects of various flavonoids have been revealed [ 148 ].…”