# METTL3 aggravates lung injury in neonatal mice with Streptococcus pneumoniae-induced pneumonia via the circ_0001239/KLF10 axis

## TL;DR

This study shows that METTL3 worsens lung damage in neonatal mice with pneumonia by affecting a specific RNA pathway, suggesting new treatment targets.

## Contribution

The study identifies a novel METTL3-regulated m6A-dependent pathway involving circ_0001239 and KLF10 in neonatal pneumonia.

## Key findings

- METTL3 and circ_0001239 are upregulated, while KLF10 is downregulated in pneumonic lungs.
- METTL3 knockdown reduces lung injury and inflammation in neonatal mice with pneumonia.
- Circ_0001239 overexpression or KLF10 knockdown reverses the protective effects of METTL3 downregulation.

## Abstract

As a leading causative agent of pneumonia infection worldwide, Streptococcus pneumoniae (Spn) induces lung injury and presents substantial therapeutic challenges. To elucidate the role of methyltransferase-like 3 (METTL3) in modulating circular RNA_0001239 (circ_0001239), YTH domain containing protein 2 (YTHDC2), and Krüppel-like factor 10 (KLF10) through m6A modification, we established Spn-induced neonatal mouse models. The survival rates, bacterial load in bronchoalveolar lavage fluid, and METTL3 expression in pulmonary tissue were evaluated. After METTL3 downregulation, lung wet-to-dry ratio, myeloperoxidase activity, and inflammatory markers were assessed. Methylated RNA immunoprecipitation detected enriched m6A modification on circ_0001239, while RNA immunoprecipitation validated the bindings of circ_0001239 to YTHDC2 and YTHDC2 to KLF10. The KLF10 mRNA stability was analyzed via actinomycin D treatment. METTL3 and circ_0001239 were upregulated in pneumonic lungs, while KLF10 was downregulated. METTL3 knockdown improved survival, alleviated lung injury, increased superoxide dismutase levels, and suppressed interleukin (IL)-6, IL-1β, and malondialdehyde levels. METTL3 promoted the binding of circ_0001239 to YTHDC2 via m6A modification, destabilizing KLF10 mRNA. Circ_0001239 overexpression or KLF10 knockdown reversed the protective effects of low expression of METTL3 on lung damage in neonatal mice with pneumonia. In conclusion, METTL3 aggravates Spn-induced lung injury via m6A-dependent circ_0001239/YTHDC2/KLF10 axis, thereby providing potential therapeutic targets for severe pneumonia.