Impact of N-acetyltransferase 10 on macrophage activation and inflammation-induced cardiac dysfunction
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Inflammation-induced cardiac dysfunction, driven by an abnormal immune response, significantly contributes to sepsis-related mortality. Controlling excessive pro-inflammatory cytokine production by immune cells remains a significant challenge. This study investigated the role of N-acetyltransferase 10 (NAT10) in macrophage activation and its contribution to inflammation-induced cardiac dysfunction. Using bone marrow-derived macrophages and an endotoxemia mouse model, we found that NAT10 is significantly upregulated in response to lipopolysaccharide (LPS) due to the deubiquitinating enzyme USP39, which stabilizes the NAT10 protein. ac4C RNA sequencing identified ETS2 as a direct target of NAT10, where the ac4C modification enhanced ETS2 mRNA stability and translation, promoting a pro-inflammatory phenotype in macrophages. NAT10 deficiency reduces LPS-induced macrophage activation and cytokine production, improving cardiac function in mice. Pharmacological inhibition of NAT10 using remodelin produced similar protective effects. Our findings reveal a novel post-transcriptional pathway and highlight the therapeutic potential of targeting NAT10 to mitigate inflammation-induced cardiac injury in endotoxemia
Date Issued
2025-07-01
Date Acceptance
2025-06-12
Citation
Cell Death and Disease, 2025, 16
ISSN
2041-4889
Publisher
Nature Publishing Group
Journal / Book Title
Cell Death and Disease
Volume
16
Copyright Statement
© The Author(s) 2025 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Identifier
10.1038/s41419-025-07796-6
Subjects
Macrophages
Animals
Mice, Inbred C57BL
Mice
Endotoxemia
Disease Models, Animal
Inflammation
Acetyltransferases
Lipopolysaccharides
Cytokines
Macrophage Activation
Male
Publication Status
Published
Article Number
471
Date Publish Online
2025-07-01