Inhibiting DNA methyltransferase DNMT3B confers protection against ferroptosis in nucleus pulposus and ameliorates intervertebral disc degeneration via upregulating SLC40A1

被引：7
作者：
Chen, Jiaxing [1 ,2 ]
Yang, Xinyu [1 ,2 ]
Li, Qiaochu [1 ,2 ]
Ma, Jingjin [1 ,2 ]
Li, Huanhuan [3 ]
Wang, Linbang [4 ]
Chen, Zhiyu [1 ,2 ]
Quan, Zhengxue [1 ,2 ,5 ]
机构：
[1] Chongqing Med Univ, Affiliated Hosp 1, Dept Orthoped, Chongqing 400016, Peoples R China
[2] Orthoped Lab Chongqing Med Univ, Chongqing 400016, Peoples R China
[3] Chongqing Univ, Gorges Hosp 3, Dept Emergency, Chongqing 404000, Peoples R China
[4] Peking Univ, Hosp 3, Dept Orthoped, Beijing 100191, Peoples R China
[5] 1 Youyi Rd, Chongqing 400016, Peoples R China
来源：
FREE RADICAL BIOLOGY AND MEDICINE | 2024年 / 220卷
基金：
中国国家自然科学基金;
关键词：
Intervertebral disc degeneration; DNMT3B; DNA methylation; Ferroptosis; OXIDATIVE STRESS; METHYLATION;
D O I：
10.1016/j.freeradbiomed.2024.05.007
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
Epigenetic changes are important considerations for degenerative diseases. DNA methylation regulates crucial genes by epigenetic mechanism, impacting cell function and fate. DNA presents hypermethylation in degenerated nucleus pulposus (NP) tissue, but its role in intervertebral disc degeneration (IVDD) remains elusive. This study aimed to demonstrate that methyltransferase mediated hypermethylation was responsible for IVDD by integrative bioinformatics and experimental verification. Methyltransferase DNMT3B was highly expressed in severely degenerated NP tissue (involving human and rats) and in -vitro degenerated human NP cells (NPCs). Bioinformatics elucidated that hypermethylated genes were enriched in oxidative stress and ferroptosis, and the ferroptosis suppressor gene SLC40A1 was identified with lower expression and higher methylation in severely degenerated human NP tissue. Cell culture using human NPCs showed that DNMT3B induced ferroptosis and oxidative stress in NPCs by downregulating SLC40A1, promoting a degenerative cell phenotype. An in -vivo rat IVDD model showed that DNA methyltransferase inhibitor 5-AZA alleviated puncture -induced IVDD. Taken together, DNA methyltransferase DNMT3B aggravates ferroptosis and oxidative stress in NPCs via regulating SLC40A1. Epigenetic mechanism within DNA methylation is a promising therapeutic biomarker for IVDD.
引用
收藏
页码：139 / 153
页数：15
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