Dimethyl fumarate alleviates high-altitude hypoxic acute lung injury by activating the NRF2/SLC7A11 axis to inhibit pulmonary epithelial ferroptosis and regulate macrophage polarization

LIU Ting; GUO Haoran; WANG Liye; HAO Zhiyun; WANG Chengbin; WANG Chi; LI Mianyang

doi:10.16016/j.2097-0927.202509088

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Dimethyl fumarate alleviates high-altitude hypoxic acute lung injury by activating the NRF2/SLC7A11 axis to inhibit pulmonary epithelial ferroptosis and regulate macrophage polarization

Basic Medicine | 更新时间：2026-01-14

- Dimethyl fumarate alleviates high-altitude hypoxic acute lung injury by activating the NRF2/SLC7A11 axis to inhibit pulmonary epithelial ferroptosis and regulate macrophage polarization
- Journal of Army Medical University Vol. 48, Issue 1, Pages: 24-41(2026)
- 作者机构：
  
  1.中国人民解放军总医院第一医学中心检验科，北京
  2.中国人民解放军医学院研究生院，北京
- 作者简介：
  
  LI Mianyang E-mail：limianyang301@126.com
- 基金信息：
  
  the National Natural Science Foundation for Young Scholars of China(82002213)
- DOI：10.16016/j.2097-0927.202509088
  CLC： R563;R594.3;R914.4
- Received：23 September 2025，
  
  Revised：2025-11-29，
  
  Accepted：14 December 2025，
  
  Published：15 January 2026
- 稿件说明：
移动端阅览
刘亭，郭浩然，王立烨，等.富马酸二甲酯通过激活NRF2/SLC7A11轴抑制肺上皮细胞铁死亡并调控巨噬细胞极化缓解高原低氧急性肺损伤［J］.陆军军医大学学报，2026，48（01）：24-41.DOI：10.16016/j.2097-0927.202509088.

LIU T，GUO H R，WANG L Y，et al.Dimethyl fumarate alleviates high-altitude hypoxic acute lung injury by activating the NRF2/SLC7A11 axis to inhibit pulmonary epithelial ferroptosis and regulate macrophage polarization［J］.J Army Med Univ，2026，48（01）：24-41.DOI：10.16016/j.2097-0927.202509088.
刘亭，郭浩然，王立烨，等.富马酸二甲酯通过激活NRF2/SLC7A11轴抑制肺上皮细胞铁死亡并调控巨噬细胞极化缓解高原低氧急性肺损伤［J］.陆军军医大学学报，2026，48（01）：24-41.DOI：10.16016/j.2097-0927.202509088. DOI：

LIU T，GUO H R，WANG L Y，et al.Dimethyl fumarate alleviates high-altitude hypoxic acute lung injury by activating the NRF2/SLC7A11 axis to inhibit pulmonary epithelial ferroptosis and regulate macrophage polarization［J］.J Army Med Univ，2026，48（01）：24-41.DOI：10.16016/j.2097-0927.202509088. DOI：

摘要

目的

探讨核因子红细胞系2相关因子2（nuclear factor erythroid 2-related factor 2，NRF2）激动剂富马酸二甲酯（dimethyl fumarate，DMF）对高原低氧急性肺损伤的保护作用，为开发高原低氧急性肺损伤预防新策略奠定基础。

方法

①SPF级5~6周龄雄性Wistar大鼠20只，体质量210~230 g，按随机数字表法分为（

=5）：常氧对照组（连续10 d腹腔注射生理盐水后置于常压常氧喂养）、低氧肺损伤组（连续10 d腹腔注射生理盐水后置于模拟海拔5 000 m的低压氧舱中暴露48 h）、DMF对照组（连续10 d腹腔注射DMF后置于常压常氧环境正常喂养）和DMF预防组（连续10 d腹腔注射DMF后置于低压氧舱中暴露48 h）。随后取大鼠肺组织用HE染色观察各组形态学变化并行肺损伤病理评分，ELISA检测炎症因子检测观察各组炎症反应，免疫荧光法检测肺组织活性氧（reactive oxygen species，ROS）水平，可见分光光度法测定谷胱甘肽（glutathione，GSH）、丙二醛（malondialdehyde， MDA）含量以及超氧化物歧化酶（super oxide dismutase，SOD）活性，Western blot和RT-qPCR检测铁死亡通路蛋白的水平变化情况。②将人支气管上皮（human bronchial epithelial， BEAS-2B）细胞和由人类外周血单核细胞（tumor human peripheral blood monocytes-1，THP-1）诱导的巨噬细胞置于常氧条件和低氧条件下共培养48 h，建立常氧对照组细胞模型和低氧肺损伤细胞模型，采用液相色谱-串联质谱法（liquid chromatography-tandem mass spectrometry，LC-MS/MS）比较常氧对照组和低氧肺损伤组BEAS-2B细胞的蛋白变化情况，并用生物信息学分析关键差异蛋白。BEAS-2B细胞预先DMF给药24 h后与THP-1细胞共培养作为DMF预防组，检测BEAS-2B细胞铁死亡相关指标及巨噬细胞极化及炎症因子分泌相关指标。在DMF干预的基础上敲低和过表达溶质载体家族7成员11（solute carrier family 7 member 11，SLC7A11）基因，检测BEAS-2B细胞的铁死亡相关指标及巨噬细胞极化和炎症因子分泌相关指标。

结果

①与低氧肺损伤组相比，DMF预防组肺组织ROS水平和MDA含量降低（

0.05），SOD活性和GSH含量升高（

0.05），SLC7A11、GSH过氧化物酶4（glutathione peroxidase 4， GPX4）表达升高（

0.05），同时肺损伤评分及炎症因子表达水平显著降低（

0.05）。②BEAS-2B细胞蛋白组学共检测出5 377个蛋白，筛选到613个差异表达蛋白（differentially expressed proteins，DEPs），包括302个上调蛋白和311个下调蛋白，9个与铁死亡相关的差异表达蛋白中SLC7A11变化最为明显。在高原低氧肺损伤的细胞模型中，与低氧肺损伤组相比，DMF预防组BEAS-2B细胞的SLC7A11、GPX4表达升高（

0.05），GSH水平及SOD活性升高，巨噬细胞M1型比例降低且炎症因子水平下降（

0.05）。③在DMF预防组基础上敲减SLC7A11后，逆转了DMF对BEAS-2B细胞MDA含量的降低（

0.05），以及SOD活性和GSH含量的升高（

0.05），且敲减SLC7A11后GPX4表达降低（

0.05），巨噬细胞M1型比例有所升高，分泌的炎症因

子水平显著升高（

0.05）。相反，过表达SLC7A11进一步增强了DMF的作用，DMF预防过表达组相较于DMF预防组BEAS-2B细胞GSH水平、SOD活性和GPX4表达显著升高（

0.05），而MDA含量显著降低（

0.05）；同时过表达SLC7A11进一步缓解了炎症反应，IL-1、IL-6、TNF-α表达水平显著降低（

0.05）。

结论

DMF通过上调NRF2/SLC7A11轴改善低氧ALI肺上皮细胞铁死亡，调控巨噬细胞极化状态并减轻炎症反应，从而对高原低氧ALI发挥保护作用。

Abstract

Objective

To investigate the protective effects of dimethyl fumarate (DMF)

an agonist of nuclear factor erythroid 2-related factor 2 (NRF2)

against acute lung injury (ALI) induced by high-altitude hypoxia

in order to found a basis for developing novel preventive strategies against hypoxic pulmonary injury.

Methods

① Twenty SPF-grade male Wistar rats (5 to 6 weeks old

210 to 230 g) were randomly divided into (

=5): normoxic control (intraperitoneal injection of normal saline for 10 consecutive days followed by being placed in a normobaric normoxia chamber)

hypoxic lung injury (intraperitoneal injection of normal saline for 10 consecutive days followed by being exposed to a hypobaric hypoxic chamber simulating 5 000 m altitude for 48 h)

DMF control (intraperitoneal injection of DMF for 10 consecutive days followed by being placed in a normobaric normoxic chamber)

and DMF prophylaxis (DMF preconditioning for 10 d followed by hypobaric hypoxic modelling) groups. HE staining was used to observe the histopathological changes in lung tissues to pathologically score the lung injury. ELISA was employed to detect the inflammatory factors to assess inflammatory responses

immunofluorescence assay was utilized to measure the generation of reactive oxygen species (ROS)

and spectrophotometry was performed to determine the glutathione (GSH) and malondialdehyde (MDA) levels

as well as superoxide dismutase (SOD) activity. Western blotting and real-time polymerase chain reaction (RT-qPCR) were applied to analyze ferroptosis

-related pathway proteins at protein and mRNA levels. ② Hypoxic lung injury cellular model and normoxic control model were established by co-culturing human bronchial epithelial (BEAS-2B) cells and TNF-α-activated human peripheral blood monocyte (THP-1)-derived macrophages under hypoxic and normoxic conditions for 48 h. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to compare the protein profiles in BEAS-2B cells between normoxic control and hypoxic injury groups. Bioinformatics analysis was carried out to identify the key differentially expressed proteins (DEPs). A hypoxic injury prophylaxis group was established by BEAS-2B cells being pretreated with DMF for 24 h and then co-cultured with THP-1 cells. Then the ferroptosis markers

macrophage polarization phenotypes

and inflammatory cytokines were detected in BEAS-2B cells. ③ Additionally

solute carrier family 7 member 11 (SLC7A11) gene was knocked down under DMF intervention to assess ferroptosis markers and macrophage-related inflammatory responses.

Results

① Compared to the hypoxic injury group

the DMF prophylaxis group exhibited significantly decreased pulmonary ROS level and MDA content (

0.05)

increased SOD activity and GSH level (

0.05)

elevated expression levels of SLC7A11 and glutathione peroxidase 4 (GPX4) (

0.05)

along with markedly reduced lung injury score and inflammatory cytokine levels (

0.05). ② Proteomic analysis identified 5 377 proteins and 613 DEPs (302 up-regulated

311 down-regulated) in BEAS-2B cells

and among 9 ferroptosis-related DEPs

SLC7A11 exhibited the most significant alteration. In the cellular hypoxic ALI model

compared to the hypoxic injury group

DMF prophylaxis up-regulated SLC7A11 and GPX4 expression (

0.05)

increased GSH level and SOD activity

decreased the M1 macrophage ratio and inflammatory factor levels (

0.05). ③ SLC7A11 knockdown rev

ersed DMF’s effects by increasing MDA level (

0.05)

decreasing SOD activity and GSH level (

0.05)

suppressing GPX4 expression (

0.05)

and elevating M1 macrophage proportion and enhancing inflammatory cytokine secretion (

0.05). Conversely

overexpression of SLC7A11 enhanced the protective effects of DMF. Compared with the hypoxia-DMF group

the hypoxia-DMF-overexpression group showed significantly increased GSH level

SOD activity

and GPX4 expression (

0.05)

along with a marked decrease in MDA content (

0.05) in BEAS-2B cells. Meanwhile

SLC7A11 overexpression further alleviated the inflammatory response

as indicated by significantly reduced expression of IL-1β

IL-6 and TNF-α (

0.05).

Conclusion

DMF attenuates high-altitude hypoxic ALI by suppressing ferroptosis in pulmonary epithelial cells

via

up-regulating the NRF2/SLC7A11 axis

modulating macrophage polarization

and mitigating inflammatory response

and thus

exerts a protective effect against hypoxic pulmonary injury.

关键词

Keywords

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