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Background <p>Sepsis-induced myocardial injury (SIMI) leads to high morbidity and mortality. The 5-methylcytosine (m<sup>5</sup>C) RNA methyltransferase NOL1/NOP2/SUN domain (NSUN)2 is a therapeutic target for many diseases. The purpose of this study was to investigate the role of NSUN2 in SIMI and the potential mechanism.</p> Methods <p>Both an in vivo cecum ligation and puncture (CLP) SIMI rat model and an in vitro lipopolysaccharide (LPS)-treated H9c2 cardiomyocytes model were established. Reverse transcription (RT)-quantitative polymerase chain reaction (qPCR) was used to detect m<sup>5</sup>C-related and ferroptosis-related mRNA levels. Enzyme-linked immunosorbent assay was performed to assess inflammatory cytokines levels. Ferroptosis-related indicators were detected by commercial kits and Western blot. Methylated RNA immunoprecipitation (MeRIP)-qPCR assay was performed to detect the m<sup>5</sup>C level of ferroptosis-related mRNAs. RIP assay was used to explore the interaction between NSUN2 and nuclear receptor coactivator (NCOA)4. The m<sup>5</sup>C site of NCOA4 was analyzed by dual-luciferase reporter assay.</p> Results <p>NSUN2 alleviated LPS-induced SIMI by increasing cell viability and inhibiting inflammation and ferroptosis. In addition, NSUN2 inhibited NCOA4 expression in a m<sup>5</sup>C-dependent manner. Moreover, overexpressing NCOA4 downregulated cell viability and upregulated LDH activity, inflammation, and ferroptosis in LPS-induced SIMI. In in vivo studies, NSUN2 overexpression reversed CLP-induced myocardial injury, cardiac dysfunction, inflammation, and ferroptosis.</p> Conclusions <p>NSUN2 inhibited NCOA4 expression to alleviate ferroptosis and inflammation in SIMI in a m<sup>5</sup>C manner, which might provide new information for the clinical treatment of SIMI.</p>

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NSUN2 inhibits NCOA4 expression to alleviate ferroptosis and inflammation in sepsis-induced myocardial injury in a m5C manner

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月28日

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  • BaYinchahan BoRanyi,
  • Xinwei Lv,
  • Dong Xiao

摘要

Background

Sepsis-induced myocardial injury (SIMI) leads to high morbidity and mortality. The 5-methylcytosine (m5C) RNA methyltransferase NOL1/NOP2/SUN domain (NSUN)2 is a therapeutic target for many diseases. The purpose of this study was to investigate the role of NSUN2 in SIMI and the potential mechanism.

Methods

Both an in vivo cecum ligation and puncture (CLP) SIMI rat model and an in vitro lipopolysaccharide (LPS)-treated H9c2 cardiomyocytes model were established. Reverse transcription (RT)-quantitative polymerase chain reaction (qPCR) was used to detect m5C-related and ferroptosis-related mRNA levels. Enzyme-linked immunosorbent assay was performed to assess inflammatory cytokines levels. Ferroptosis-related indicators were detected by commercial kits and Western blot. Methylated RNA immunoprecipitation (MeRIP)-qPCR assay was performed to detect the m5C level of ferroptosis-related mRNAs. RIP assay was used to explore the interaction between NSUN2 and nuclear receptor coactivator (NCOA)4. The m5C site of NCOA4 was analyzed by dual-luciferase reporter assay.

Results

NSUN2 alleviated LPS-induced SIMI by increasing cell viability and inhibiting inflammation and ferroptosis. In addition, NSUN2 inhibited NCOA4 expression in a m5C-dependent manner. Moreover, overexpressing NCOA4 downregulated cell viability and upregulated LDH activity, inflammation, and ferroptosis in LPS-induced SIMI. In in vivo studies, NSUN2 overexpression reversed CLP-induced myocardial injury, cardiac dysfunction, inflammation, and ferroptosis.

Conclusions

NSUN2 inhibited NCOA4 expression to alleviate ferroptosis and inflammation in SIMI in a m5C manner, which might provide new information for the clinical treatment of SIMI.