Sirt1 is involved in intervertebral disc degeneration <italic style="font-style: italic">via</italic> regulating histone H3K18 lactylation in nucleus pulposus cells

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Sirt1 is involved in intervertebral disc degeneration via regulating histone H3K18 lactylation in nucleus pulposus cells

Basic Medicine | 更新时间：2025-12-30

- Sirt1 is involved in intervertebral disc degeneration via regulating histone H3K18 lactylation in nucleus pulposus cells
- Journal of Army Medical University Vol. 47, Issue 24, Pages: 3045-3055(2025)
- 作者机构：
  
  陆军军医大学（第三军医大学）第二附属医院骨科，重庆
- 作者简介：
  
  LIU Minghan，E-mail：liuminghan@tmmu.edu.cn
  LI Changqing，E-mail： changqli@tmmu.edu.cn
- 基金信息：
  
  the National Natural Science Foundation of China(82472517;82472445);the Natural Science Foundation of Chongqing(CSTB2024NSCQ-KJFZMSX0052)
- DOI：10.16016/j.2097-0927.202509085
  CLC： R394.3;R363.21;R681.53
- Received：24 September 2025，
  
  Revised：2025-12-09，
  
  Published：30 December 2025
- 稿件说明：
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欧阳健，翟羽，张雨尧，等.Sirt1通过调控髓核细胞组蛋白H3K18乳酸化参与椎间盘退变的机制研究［J］.陆军军医大学学报，2025，47（24）：3045-3055.DOI：10.16016/j.2097-0927.202509085.

OUYANG J，ZHAI Y，ZHANG Y Y，et al.Sirt1 is involved in intervertebral disc degeneration via regulating histone H3K18 lactylation in nucleus pulposus cells［J］.J Army Med Univ，2025，47（24）：3045-3055.DOI：10.16016/j.2097-0927.202509085.
欧阳健，翟羽，张雨尧，等.Sirt1通过调控髓核细胞组蛋白H3K18乳酸化参与椎间盘退变的机制研究［J］.陆军军医大学学报，2025，47（24）：3045-3055.DOI：10.16016/j.2097-0927.202509085. DOI：

OUYANG J，ZHAI Y，ZHANG Y Y，et al.Sirt1 is involved in intervertebral disc degeneration via regulating histone H3K18 lactylation in nucleus pulposus cells［J］.J Army Med Univ，2025，47（24）：3045-3055.DOI：10.16016/j.2097-0927.202509085. DOI：

摘要

目的

2

探究沉默信息调节蛋白1（sirtuin 1，Sirt1）调节H3K18乳酸化（H3K18la）对髓核细胞（nucleus pulposus cells，NPCs）的影响以及在椎间盘退变（intervertebral disc degeneration，IVDD）中的作用。

方法

2

构建大鼠尾椎椎间盘针刺诱导退变（puncture-induced intervertebral disc degeneration，PIDD）模型；并通过组织学染色、生化检测、流式细胞术与蛋白质免疫印迹（Western blot）评估正常对照（NC）组和针刺退变（PIDD）组椎间盘退变程度及乳酸（La）、丙二醛（MDA）、活性氧（ROS）、H3K18la与Sirt1表达水平；在NPCs中，分别采用梯度浓度La处理及慢病毒介导的Sirt1敲低与过表达，通过免疫荧光与生化检测分析H3K18la、ROS与MDA水平；利用靶向切割与转座标记（cleavage under targets and tagmentation，CUT&Tag）技术及生物信息技术分析H3K18la调控的基因及相关通路；24只大鼠均分为4个分组：正常对照（NC）组、针刺退变（PIDD）组、针刺治疗（PIDD+oe-Sirt1）组、针刺病毒对照（PIDD+Vector）组，验证过表达Sirt1对椎间盘退变的干预作用。

结果

2

与NC组相比，PIDD组组织学评分、La、ROS及MDA水平均显著升高（

P<

0.01），同时，PIDD组中H3K18la表达升高（

P<

0.01），而Sirt1表达下降（

P<

0.01）；在细胞实验中，H3K18la、ROS及MDA水平随La浓度增加呈浓度依赖性升高；Sirt1过表达可降低H3K18la表达（

P<

0.01），敲低则使其升高（

P<

0.01）；CUT

&

Tag技术检测提示H3K18la可能调控髓核细胞氧化应激；在动物实验中，与PIDD组及PIDD+Vector组相比，PIDD+oe-Sirt1组组织学评分、ROS、H3K18la及MDA水平均显著降低（

P<

0.01）。

结论

2

退变椎间盘中Sirt1的表达明显下降，Sirt1是组蛋白H3K18la去乳酸化修饰酶，Sirt1调控的组蛋白H3K18la的乳酸化修饰可能调节髓核细胞氧化应激，进而调控椎间盘退变。

Abstract

Objective To explore the effect of Sirtuin 1 (Sirt1) on nucleus pulposus cells (NPCs) by regulating histone H3K18 lactylation and its implications for intervertebral disc degeneration (IVDD). Methods Puncture-induced intervertebral disc degeneration (PIDD) was modeled in the rat caudal vertebrae. The severity of disc degeneration was evaluated

and the expression levels of lactic acid (La)

malondialdehyde (MDA)

reactive oxygen species (ROS)

H3K18la

and Sirt1 were detected in both the normal control (NC) group and the PIDD group using histopathological staining

biochemical assay

flow cytometry

and Western blot analysis. Gradient concentrations of La were used to treat NPCs

and Sirt1 was knocked down or overexpressed

via

lentiviral transduction. Changes in H3K18la

ROS

and MDA levels were analyzed by immunofluorescence and biochemical assays. The genes regulated by H3K18la and their associated pathways were identified using Cleavage Under Targets and Tagmentation (CUT

&

Tag) and bioinformatic analyses. Then 24 rats were assigned into normal control (NC)

PIDD

PIDD with Sirt1 overexpression (PIDD+oe-Sirt1)

and PIDD with viral control (PIDD+Vector) groups

in order to assess the therapeutic effect of Sirt1 overexpression on intervertebral disc degeneration.

Results

2

The P

IDD group had significantly higher histological scores and elevated levels of La

ROS

and MDA

and enhanced expression of H3K18la but decreased Sirt1 expression when compared with the NC group (

P

<

0.01). In cellular experiments

H3K18la

ROS

and MDA levels were in a concentration-dependent increase with the increments of La concentration. Sirt1 overexpression significantly reduced H3K18la expression (

P

<

0.01)

whereas its knockdown conversely increased it (

P

<

0.01). CUT

&

Tag analysis indicated that H3K18la plays a regulatory role in oxidative stress in NPCs. In animal experiments

the PIDD+oe-Sirt1 group exhibited significantly lower histological scores

along with reduced levels of ROS

H3K18la

and MDA in comparison to the PIDD and PIDD+Vector groups (

P

<

0.01). Conclusion The expression of Sirt1 is significantly decreased in degenerative intervertebral discs. As a delactylase for histone H3K18la

Sirt1 may play a critical role in intervertebral disc degeneration by modulating oxidative stress in nucleus pulposus cells through H3K18la lactylation.

关键词

Keywords

references

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