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Targeting NAT10 to surpress ferroptosis and attenuate skin fibrosis progression

ABSTRACT: Abstract Background: N-acetyltransferase 10 (NAT10) is a unique RNA acetyltransferase responsible for catalyzing N4-acetylcytidine (ac4C) modifications on mRNA, influencing RNA stability and translation. While NAT10 has been implicated in fibrosis of other organs, its role in skin fibrosis and ferroptosis regulation remains poorly understood. This study aimed to investigate the involvement of NAT10 in fibroblast activation and skin fibrotic remodeling via modulation of ferroptosis. Methods: The expression of NAT10 was assessed in bleomycin-induced fibrotic mouse skin tissues and TGF-β1-stimulated fibroblasts. Functional experiments, including wound healing, transwell migration, and EdU staining, were performed following NAT10 knockdown. The impact of NAT10 on ferroptosis was evaluated by measuring lipid ROS, GSH, and MDA levels, along with key ferroptosis markers such as GPX4, SLC7A11, and TFR1. RNA-seq and bioinformatic analyses identified MAP1LC3A as a downstream target. The effects of NAT10 inhibition were further validated in vivo using Remodelin and Erastin interventions. Results: NAT10 expression and ac4C RNA modification were upregulated in fibrotic skin tissues and activated fibroblasts. Silencing NAT10 impaired fibroblast proliferation and migration, alleviated fibrosis, and reduced ferroptosis-related oxidative stress both in vitro and in vivo. Mechanistically, NAT10 knockdown decreased MAP1LC3A stability, leading to suppressed ferroptosis. Pharmacological modulation with Erastin partially reversed the antifibrotic effects of NAT10 inhibition, underscoring the involvement of ferroptosis in this process. Conclusions: Our findings demonstrate that NAT10 contributes to skin fibrosis by promoting ferroptosis through the regulation of MAP1LC3A stability. Targeting NAT10 may offer a promising therapeutic approach for fibrotic skin diseases. Keywords: Skin Fibrosis, Ferroptosis, NAT10, Fibroblast

ORGANISM(S): Homo sapiens

PROVIDER: GSE297275 | GEO | 2026/06/01

REPOSITORIES: GEO

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Project description:Background: Heart failure (HF), characterized by cardiac remodeling, is associated with abnormal epigenetic processes and aberrant gene expression. Here, we aimed to elucidate the effects and mechanisms of N-acetyltransferase 10 (NAT10)-mediated N4?acetylcytidine (ac4C) acetylation during cardiac remodeling. Methods: NAT10 and ac4C expression were detected in both human and mouse subjects with cardiac remodeling through multiple assays. Subsequently, acetylated RNA immunoprecipitation and sequencing (acRIP-seq), thiol (SH)-linked alkylation for the metabolic sequencing of RNA (SLAM-seq), and ribosome sequencing (Ribo-seq) were employed to elucidate the role of ac4C-modified post-transcriptional regulation in cardiac remodeling. Additionally, functional experiments involving the overexpression or knockdown of NAT10 were conducted in mice models challenged with Ang II and transverse aortic constriction (TAC). Results: NAT10 expression and RNA ac4C levels were increased in in vitro and in vivo cardiac remodeling models, as well as in patients with cardiac hypertrophy. Silencing and inhibiting NAT10 attenuated Ang II-induced cardiomyocyte hypertrophy and cardio-fibroblast activation. Next-generation sequencing revealed ac4C changes in both mice and humans with cardiac hypertrophy were associated with changes in global mRNA abundance, stability and translation efficiency. Mechanistically, NAT10 could enhance the stability and translation efficiency of CD47 and ROCK2 transcripts by upregulating their mRNA ac4C modification, thereby resulting in an increase in their protein expression during cardiac remodeling. Furthermore, the administration of Remodelin, a NAT10 inhibitor, has been shown to prevent cardiac functional impairments in mice subjected to TAC by suppressing cardiac fibrosis, hypertrophy, and inflammatory responses, while also regulating the expression levels of CD47 and ROCK2. Conclusions: Therefore, our data suggest that modulating epitranscriptomic processes, such as ac4C acetylation through NAT10, may be a promising therapeutic target against cardiac remodeling.

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Targeting NAT10 to surpress ferroptosis and attenuate skin fibrosis progression

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