# Mettl3‐Mediated m6A Modification Represents a Novel Therapeutic Target for FSGS

## TL;DR

This study shows that Mettl3-mediated m6A modifications are crucial for podocyte function and could be a new treatment target for FSGS.

## Contribution

The study identifies Mettl3 as a novel therapeutic target for FSGS through its role in m6A modification and the TJP1–CDC42 pathway.

## Key findings

- Reduced m6A levels in podocytes correlate with FSGS in both mice and patients.
- Mettl3 deficiency causes slit diaphragm dysfunction and FSGS-like symptoms in mice.
- m6A-mimic compounds reduce FSGS progression in mouse models.

## Abstract

Focal segmental glomerulosclerosis (FSGS) is a common glomerular lesion that manifests as a primary podocyte injury. Multiple genetic risk factors have been reported to be associated with the development of FSGS. However, whether epigenetic factors, especially N6‐methyladenosine (m6A) modifications, are involved in the pathogenesis of FSGS remains unclear. By generating a mouse line with a specific deletion of N6‐adenosine‐methyltransferase‐like 3 (Mettl3) in podocytes (Mettl3
podkomice), podocytes are isolated and performed RNA‐seq. It is shown that RNA m6A methylation levels are reduced in the renal glomeruli of both animal models and patients with FSGS. A significant decrease in RNA m6A levels in podocytes and the development of an FSGS phenotype are observed in the Mettl3
podko mice. Furthermore, RNA‐seq and m6A‐immunoprecipitated RNA sequencing revealed that silencing Mettl3 expression in podocytes led to a gene expression profile associated with slit diaphragm dysfunction. RNA immunoprecipitation assay and hybridization chain reaction (HCR) analysis further identified the slit diaphragm marker TJP1 as a potential target of Mettl3. Moreover, loss‐ and gain‐of‐function analyses showed that Mettl3 enhances podocyte RNA m6A modification, probably through the TJP1–CDC42 pathway. Finally, treatment of Mettl3
podko and adriamycin (ADR)‐induced FSGS mice with m6A‐mimic compounds markedly ameliorated the progression of FSGS. The findings demonstrate that Mettl3‐mediated RNA m6A modification is essential for maintaining podocyte architecture and function and represents a potential therapeutic target for FSGS.

This study explores the roles of Mettl3‐induced N6‐methyladenosine (m6A) modifications in Focal segmental glomerulosclerosis (FSGS). The findings reveal that inhibition of Mettl3 results in podocyte injury by modulating the TJP1CDC42 pathway. Moreover, Administration of N6‐methyladenosine attenuates the FSGS phenotype in WT mice induced by Adriamycin and Mettl3 deficiency.