Vitamin D3 inhibits nitrogen mustard-induced keratinocyte ferroptosis by activating Nrf2

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Vitamin D3 inhibits nitrogen mustard-induced keratinocyte ferroptosis by activating Nrf2

Military Medicine | 更新时间：2025-04-14

- Vitamin D3 inhibits nitrogen mustard-induced keratinocyte ferroptosis by activating Nrf2
- Journal of Army Medical University Vol. 47, Issue 7, Pages: 674-680(2025)
- 作者机构：
  
  1.陆军军医大学（第三军医大学）：军事预防医学系防化医学教研室，重庆
  2.陆军军医大学（第三军医大学）：创伤与化学中毒全国重点实验室，重庆
- 作者简介：
  
  CHEN Mingliang， E-mail： chenmingliang1987@163.com
- 基金信息：
  
  the Open Project of State Key Laboratory of Trauma and Chemical Poisoning(SKL0202407)
- DOI：10.16016/j.2097-0927.202409076
  CLC： R963;R977.24;R9964
- Received：12 September 2024，
  
  Revised：20 February 2025，
  
  Published：15 April 2025
- 稿件说明：
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董训虎,刘浩银,葛维,等.维生素D3通过激活Nrf2抑制氮芥诱导角质形成细胞铁死亡的作用研究[J].陆军军医大学学报,2025,47(07):674-680.

DONG Xunhu,LIU Haoyin,GE Wei,et al.Vitamin D3 inhibits nitrogen mustard-induced keratinocyte ferroptosis by activating Nrf2[J].J Army Med Univ,2025,47(07):674-680.
董训虎,刘浩银,葛维,等.维生素D3通过激活Nrf2抑制氮芥诱导角质形成细胞铁死亡的作用研究[J].陆军军医大学学报,2025,47(07):674-680. DOI：10.16016/j.2097-0927.202409076.

DONG Xunhu,LIU Haoyin,GE Wei,et al.Vitamin D3 inhibits nitrogen mustard-induced keratinocyte ferroptosis by activating Nrf2[J].J Army Med Univ,2025,47(07):674-680. DOI：10.16016/j.2097-0927.202409076.

摘要

目的

2

探索铁死亡在维生素D3（vitamin D3，VD3）改善氮芥（nitrogen mustard，NM）诱导角质形成细胞（HaCaT）毒性损伤中的作用及机制。

方法

2

采用梯度浓度NM（5、10、20和50 μmol/L）单独或联合铁死亡抑制剂ferrostatin-1或liproxstatin-1（10 μmol/L）、核因子-E2相关因子2（nuclear factor E2 related factor 2，Nrf2）特异性激动剂tBHQ（10 μmol/L）、VD3（10 nmol/L）处理HaCaT细胞。共培养24 h后，分别检测细胞增殖活力、细胞内谷胱甘肽（glutathione， GSH）和脂质过氧化物（malondialdehyde，MDA）含量，以及Nrf2、xCT和GPX4等蛋白的表达水平。

结果

2

NM以浓度依赖性方式抑制HaCaT细胞增殖活力，当NM浓度为20 μmol/L时，细胞增殖活力下降至约55%（

P

<

0.05）。铁死亡抑制剂能够减轻NM诱导的HaCaT细胞毒性损伤（

P

<

0.05）。此外，激活Nrf2可显著抑制NM对HaCaT细胞铁死亡的诱导效应，表现为细胞内GSH水平的恢复和MDA含量的降低（

P

<

0.05）。同时，VD3能够靶向激活Nrf2信号通路，上调xCT和GPX4蛋白的表达，从而有效抑制HaCaT细胞的铁死亡，并缓解NM诱导的细胞毒性。

结论

2

VD3通过激活Nrf2抑制HaCaT细胞铁死亡，进而改善NM诱导的细胞毒性损伤。

Abstract

Objective‍　‍To explore the role and mechanism of ferroptosis in vitamin D3 (VD3) improving the cytotoxicity of keratinocytes (HaCaT cells) induced by nitrogen mustard (NM). Methods‍　‍HaCaT cells were treated with gradient concentrations of NM (5

10

20

and 50 μmol/L) alone or in combination with ferroptosis inhibitor ferrostatin-1 or liproxstatin-1 (10 μmol/L)

Nrf2-specific agonist tBHQ (10 μmol/L)

and VD3 (10 nmol/L)

respectively. After co-culture for 24 h

cell viability was assessed

and the intracellular contents of glutathione (GSH) and malondialdehyde (MDA) were measured. Additionally

the expression levels of Nrf2

xCT

and GPX4 were detected. Results‍　‍NM exerted inhibitory effect on the proliferation of HaCaT cells in a dose-dependent manner

and the cell viability was reduced to approximately 55% at an NM concentration of 20 μmol/L (

P

<

0.05). Ferroptosis inhibitors significantly mitigated the cytotoxic damage induced by NM in HaCaT cells (

P

<

0.05)

but activation of nuclear factor E2 related factor 2（Nrf2） markedly attenuated NM-induced ferroptosis

as indicated by the restoration of intracellular GSH level and the decrease in MDA content (

P

<

0.05). VD3 specifically targeted the Nrf2 signaling pathway

upregulated the expression of xCT and GPX4 protein

thereby inhibiting ferroptosis and reducing NM-induced cytotoxicity in HaCaT cells. Conclusion‍　‍VD3 mitigates NM-induced cytotoxicity in HaCaT cells by inhibiting ferroptosis

via

Nrf2 activation.

关键词

Keywords

references

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