MiR-21-5p alleviates hyperoxia-induced acute lung injury by inhibiting ferroptosis through the STAT3/P53/SLC7A11 axis

ZHOU Xiangui; JIANG Yuwei; LIU Xinxin; YU Kun; QIN Song; LIU Xiaofei; FENG Banghai

doi:10.16016/j.2097-0927.202509017

您当前的位置：

首页 >

文章列表页 >

MiR-21-5p alleviates hyperoxia-induced acute lung injury by inhibiting ferroptosis through the STAT3/P53/SLC7A11 axis

Basic Medicine | 更新时间：2025-12-25

- MiR-21-5p alleviates hyperoxia-induced acute lung injury by inhibiting ferroptosis through the STAT3/P53/SLC7A11 axis
- Journal of Army Medical University Vol. 47, Issue 20, Pages: 2474-2482(2025)
- 作者机构：
  
  1.遵义医科大学附属医院：急诊科，贵州遵义
  3.遵义医科大学附属医院：重症医学科，贵州遵义
  2.遵义市中医院重症医学科，贵州遵义
- 作者简介：
- 基金信息：
  
  the Regional Science Fund Program of National Natural Science Foundation of China(81960362);the General Project of Natural Science Foundation of Guizhou Province;the Project of Science and Technology Fund of Guizhou Provincial Health Commission(gzwkj2024-310);the General Project of Zunyi Science and Technology and Big Data Bureau(遵市科合HZ字（2023）199号)
- DOI：10.16016/j.2097-0927.202509017
  CLC： R394.3;R563.05;R966
- Received：04 September 2025，
  
  Revised：2025-10-09，
  
  Accepted：09 October 2025，
  
  Published：30 October 2025
- 稿件说明：
移动端阅览
周先贵，江雨薇，刘鑫鑫，等.微小RNA-21-5p通过STAT3/P53/SLC7A11轴抑制铁死亡减轻高氧性急性肺损伤［J］.陆军军医大学学报，2025，47（20）：2474-2482.DOI：10.16016/j.2097-0927.202509017.

ZHOU X G，JIANG Y W，LIU X X，et al.MiR-21-5p alleviates hyperoxia-induced acute lung injury by inhibiting ferroptosis through the STAT3/P53/SLC7A11 axis［J］.J Army Med Univ，2025，47（20）：2474-2482.DOI：10.16016/j.2097-0927.202509017.
周先贵，江雨薇，刘鑫鑫，等.微小RNA-21-5p通过STAT3/P53/SLC7A11轴抑制铁死亡减轻高氧性急性肺损伤［J］.陆军军医大学学报，2025，47（20）：2474-2482.DOI：10.16016/j.2097-0927.202509017. DOI：

ZHOU X G，JIANG Y W，LIU X X，et al.MiR-21-5p alleviates hyperoxia-induced acute lung injury by inhibiting ferroptosis through the STAT3/P53/SLC7A11 axis［J］.J Army Med Univ，2025，47（20）：2474-2482.DOI：10.16016/j.2097-0927.202509017. DOI：

摘要

目的

探讨微小miR-21-5p（microRNA-21-5p，miR-21）是否通过STAT3/P53/SLC7A11轴调控铁死亡在高氧性急性肺损伤（hyperoxia-induced acute lung injury，HALI）发挥肺保护作用。

方法

采用免疫共沉淀技术（co-immunoprecipitation， Co-IP）分析STAT3与P53的相互作用。选择50只9周龄C57BL/6J雄性小鼠，按随机数字表法分为常氧（Control）组、高氧（HALI）组、miR-21过表达（miR-21）组、STAT3抑制剂（HY-13818）组及铁抑素-1（ferrostatin-1，Fer-1）组。Control组置于室内空气中饲养；miR-21组经气管导管滴入miR-21 AAV6载体，饲养3周；HY-13818组以10 mg/kg经腹腔注射，每周3次，干预2周；Fer-1组在造模时以0.8 mg/kg ferrostatin-1经尾静脉注射，每天1次，干预2次；吸入90%以上浓度氧气建立HALI小鼠模型。高氧暴露48 h后，眼球采血RT-PCR检测miR-21表达水平；取肺组织计算肺W

湿质量

干质量

，HE染色光镜下观察形态学变化并行肺损伤病理评分；光电比色法测定超氧化物歧化酶（superoxide dismutase，SOD）水平，可见分光光度法测定丙二醛（malondialdehyde，MDA）、Fe

及谷胱甘肽（glutathione，GSH）浓度，荧光分光光度法测定活性氧（ROS）水平；Western blot法检测肺组织STAT3、P53、SLC7A11及GPX4蛋白相对表达水平。

结果

Co-IP结果显示，STAT3可与P53结合。HALI组HE染色可见肺泡结构破坏、排列紊乱、间隔明显增厚伴大量中性粒细胞细胞浸润，肺泡萎陷，与Control组比较，肺损伤病理评分及肺W

湿质量

干质量

显著增高（

0.05）；HE染色结果显示，miR-21组、HY-13818组及Fer-1组肺损伤程度较HALI明显减轻，肺损伤病理评分及W

湿质量

干质量

比显著降低（

0.05）。与Control组比较，HALI组MDA、Fe

及ROS水平升高（

0.05），SOD、GSH水平降低（

0.05），STAT3及P53蛋白表达升高（

0.05），SLC7A11及GPX4蛋白表达下降（

0.05）；与HALI组比较，miR-21组和HY-13818组MDA、ROS水平降低（

0.05），SOD、Fe

及GSH水平升高（

0.05），STAT3、P53表达降低（

0.05），SLC7A11及GPX4蛋白升高（

0.05）。

结论

miR-21减轻高氧性急性肺损伤，可能与其通过STAT3/P53/SLC7A11轴抑制铁死亡相关。

Abstract

Objective

To investigate whether microRNA-21-5p (miR-21) plays a protective role in hyperoxia-induced acute lung injury (HALI) by regulating ferroptosis through the STAT3/P53/SLC7A11 axis.

Methods

The interaction between STAT3 and P53 was analyzed by co-immunoprecipitation (Co-IP). Fifty 9-week-old male C57BL/6J mice were randomly divided into normoxia (Control) group

HALI group

miR-21 overexpression (m

iR-21) group

STAT3 inhibitor (HY-13818) group

and ferrostatin-1 (Fer-1) group. After the mice from the miR-21 group received miR-21-5p AAV6 or empty vector

via

tracheal catheter instillation

the animals were then monitored for 3 weeks. The HY-13818 group was intraperitoneally injected with HY-13818 (10 mg/kg) 3 times weekly for 2 weeks. The Fer-1 group received 0.8 mg/kg ferrostatin-1

via

tail vein injection once daily for 2 consecutive days during modeling. The HALI model was established by exposure to

90% oxygen. After 48 h of hyperoxia

blood samples were collected

via

orbital sampling for RT-PCR analysis of miR-21 expression. Lung tissues were harvested for wet/dry weight ratio and assessment of histopathological changes

via

HE staining for lung injury score. Activity of superoxide dismutase (SOD) and contents of malondialdehyde (MDA)

Fe²⁺

glutathione (GSH)

and reactive oxygen species (ROS) were measured using photocolorimetry

spectrophotometry and fluorometry. Western blotting was used to evaluate the protein expression of STAT3

P53

SLC7A11

and GPX4.

Results

The results of Co-IP showed that STAT3 could bind to P53. The HALI group exhibited obviously destroyed alveolar structure

disordered arrangement

thickened interval

with a large number of infiltrated neutrophils and collapsed alveoli

and had significantly increased pathological score of lung injury and ratio of lung W

wet

dry

weight when compared with the Control group (

0.05). In the miR-21 group

HY-13818 group and Fer-1 group

the severity of lung injury was significantly reduced

and the pathological score of lung injury and the ratio of W

wet

dry

weight were decreased (

0.05) when compared with the HALI group. Compared with the control group

the contents of MDA

and ROS were increased (

0.05)

the activity of SOD

and content of GSH were declined (

0.05)

the protein levels of STAT3 and P53 were increased (

0.05)

and those of SLC7A11 and GPX4 were decreased (

0.05) in the HALI group. Compared with the HALI group

decreased MDA and ROS levels (

0.05)

enhanced SOD activity

and GSH levels (

0.05)

down-regulation of STAT3 and P53 (

0.05) and up-regulation of SLC7A11 and GPX4 (

0.05) were observed in the miR-21 group and HY-13818 group.

Conclusion

MiR-21 alleviates HALI

which may be related to its inhibition of ferroptosis through the STAT3/P53/SLC7A11 axis.

关键词

Keywords

references

YAMAMOTO R ， FUJISHIMA S ， YAMAKAWA K ， et al . Hyperoxia for sepsis and development of acute lung injury with increased mortality ［J］. BMJ Open Respir Res ， 2023 ， 10 （ 1 ）： e001968 . DOI： 10.1136/bmjresp-2023-001968 http://dx.doi.org/10.1136/bmjresp-2023-001968 .

冯帮海，刘国跃，覃松，等 . 自噬在急性肺损伤/急性呼吸窘迫综合征作用机制中的研究进展［J］. 中国中西医结合急救杂志， 2019 ， 26 （ 2 ）： 242 - 246 . DOI： 10.3969/j.issn.1008-9691.2019.02.028 http://dx.doi.org/10.3969/j.issn.1008-9691.2019.02.028 .

FENG B H ， LIU G Y ， QIN S ， et al . Research progress on autophagic mechanism in acute lung injury/acute respiratory distress syndrome ［J］. Chin J TCM WM Crit Care ， 2019 ， 26 （ 2 ）： 242 - 246 . DOI： 10.3969/j.issn.1008-9691.2019.02.028 http://dx.doi.org/10.3969/j.issn.1008-9691.2019.02.028 .

冯帮海，梅鸿，覃松，等 . 铁死亡在急性呼吸窘迫综合征作用机制中的研究进展［J］. 中国现代医学杂志， 2022 ， 32 （ 13 ）： 63 - 68 . DOI： 10.3969/j.issn.1005-8982.2022.13.011 http://dx.doi.org/10.3969/j.issn.1005-8982.2022.13.011 .

FENG B H ， MEI H ， QIN S ， et al . Research progress on the mechanism of ferroptosis in acute respiratory distress syndrome ［J］. China J Mod Med ， 2022 ， 32 （ 13 ）： 63 - 68 . DOI： 10.3969/j.issn.1005-8982.2022.13.011 http://dx.doi.org/10.3969/j.issn.1005-8982.2022.13.011 .

郭浩然，刘亭，王立烨，等 . 铁抑素-1通过抑制肺上皮细胞铁死亡减轻高原低氧肺损伤炎症反应［J］. 陆军军医大学学报， 2025 ， 47 （ 12 ）： 1261 - 1275 . DOI： 10.16016/j.2097-0927.202502011 http://dx.doi.org/10.16016/j.2097-0927.202502011 .

GUO H R ， LIU T ， WANG L Y ， et al . Ferrostatin-1 attenuates inflammatory response to hypoxic lung injury at plateau by inhibiting ferroptosis in lung epithelial cells ［J］. J Amry Med Univ ， 2025 ， 47 （ 12 ）： 1261 - 1275 . DOI： 10.16016/j.2097-0927.202502011 http://dx.doi.org/10.16016/j.2097-0927.202502011 .

ZHOU X Q ， TIAN L ， XIONG W Y ， et al . Ferroptosis and hyperoxic lung injury： insights into pathophysiology and treatment approaches ［J］. Front Pharmacol ， 2025 ， 16 ： 1568246 . DOI： 10.3389/fphar.2025.1568246 http://dx.doi.org/10.3389/fphar.2025.1568246 .

ZHU M Y ， PENG L L ， HUO S Q ， et al . STAT3 signaling promotes cardiac injury by upregulating NCOA4-mediated ferritinophagy and ferroptosis in high-fat-diet fed mice ［J］. Free Radic Biol Med ， 2023 ， 201 ： 111 - 125 . DOI： 10.1016/j.freeradbiomed.2023.03.003 http://dx.doi.org/10.1016/j.freeradbiomed.2023.03.003 .

TAO Y M ， XU X X ， YANG B ， et al . Mitigation of sepsis-induced acute lung injury by BMSC-derived exosomal miR-125b-5p through STAT3-mediated suppression of macrophage pyroptosis ［J］. Int J Nanomed ， 2023 ， 18 ： 7095 - 7113 . DOI： 10.2147/IJN.S441133 http://dx.doi.org/10.2147/IJN.S441133 .

ZHANG Y P ， XIE J . Ferroptosis-related exosomal non-coding RNAs： promising targets in pathogenesis and treatment of non-malignant diseases ［J］. Front Cell Dev Biol ， 2024 ， 12 ： 1344060 . DOI： 10.3389/fcell.2024.1344060 http://dx.doi.org/10.3389/fcell.2024.1344060 .

任颖聪，陈淼，刘鑫鑫，等 . 胞外囊泡微小RNA在急性肺损伤中的相关研究进展［J］. 中华危重病急救医学， 2021 ， 33 （ 5 ）： 633 - 637 . DOI： 10.3760/cma.j.cn121430-20200727-00544 http://dx.doi.org/10.3760/cma.j.cn121430-20200727-00544 .

REN Y C ， CHEN M ， LIU X X ， et al . Research progress of extracellular vesicle microRNA in acute lung injury ［J］. Chin Crit Care Med ， 2021 ， 33 （ 5 ）： 633 - 637 . DOI： 10.3760/cma.j.cn121430-20200727-00544 http://dx.doi.org/10.3760/cma.j.cn121430-20200727-00544 .

DING Y ， HOU Y P ， LIU Y H ， et al . Prospects for miR-21 as a target in the treatment of lung diseases ［J］. Curr Pharm Des ， 2021 ， 27 （ 3 ）： 415 - 422 . DOI： 10.2174/1381612826999 200820160608 http://dx.doi.org/10.2174/1381612826999200820160608 .

周先贵，蒋艳，韩梅，等 . miR21-5p靶向转录激活蛋白STAT3减轻高氧性急性肺损伤［J］. 实用医学杂志， 2023 ， 39 （ 1 ）： 21 - 27 . DOI： 10.3969/j.issn.1006-5725.2023.01.004 http://dx.doi.org/10.3969/j.issn.1006-5725.2023.01.004 .

ZHOU X G ， JIANG Y ， HAN M ， et al . miR21-5p targets transcriptional activator protein STAT3 to alleviate hyperoxia-induced acute lung injury ［J］. J Pract Med ， 2023 ， 39 （ 1 ）： 21 - 27 . DOI： 10.3969/j.issn.1006-5725.2023.01.004 http://dx.doi.org/10.3969/j.issn.1006-5725.2023.01.004 .

冯帮海，任颖聪，袁平，等 . Ⅱ型肺泡上皮细胞来源外泌体miR-21-5p调控上皮钠离子通道减轻高氧性急性肺损伤［J］. 陆军军医大学学报， 2023 ， 45 （ 21 ）： 2222 - 2230 . DOI： 10.16016/j.2097-0927.202212027 http://dx.doi.org/10.16016/j.2097-0927.202212027 .

FENG B H ， REN Y C ， YUAN P ， et al . Exosomal miR-21-5p derived from typeⅡalveolar epithelial cells alleviates hyperoxia-induced acute lung injury by regulating epithelial sodium channels in mice ［J］. J Army Med Univ ， 2023 ， 45 （ 21 ）： 2222 - 2230 . DOI： 10.16016/j.2097-0927.202212027 http://dx.doi.org/10.16016/j.2097-0927.202212027 .

刘国跃，牟胜旭，陈淼，等 . 一种简便可控的高氧急性肺损伤模型的建立方法［J］. 中华危重病急救医学， 2016 （ 1 ）： 27 - 32 . DOI： 10.3760/cma.j.issn.2095-4352.2016.01.006 http://dx.doi.org/10.3760/cma.j.issn.2095-4352.2016.01.006 .

LIU G Y ， MOU S X ， CHEN M ， et al . A simple and controllable method for reproduction of a model of high oxygen tension induced acute lung injury ［J］. Chin Crit Care Med ， 2016 （ 1 ）： 27 - 32 . DOI： 10.3760/cma.j.issn.2095-4352.2016.01.006 http://dx.doi.org/10.3760/cma.j.issn.2095-4352.2016.01.006 .

MATUTE-BELLO G ， DOWNEY G ， MOORE B B ， et al . An official American Thoracic Society workshop report： features and measurements of experimental acute lung injury in animals ［J］. Am J Respir Cell Mol Biol ， 2011 ， 44 （ 5 ）： 725 - 738 . DOI： 10.1165/rcmb.2009-0210ST http://dx.doi.org/10.1165/rcmb.2009-0210ST .

BAIK A H ， HARIBOWO A G ， CHEN X W ， et al . Oxygen toxicity causes cyclic damage by destabilizing specific Fe-S cluster-containing protein complexes ［J］. Mol Cell ， 2023 ， 83 （ 6 ）： 942 - 960.e9 . DOI： 10.1016/j.molcel.2023.02.013 http://dx.doi.org/10.1016/j.molcel.2023.02.013 .

QIN S ， LIU J Y ， WANG X Q ， et al . ROS-med iated MAPK activation aggravates hyperoxia-induced acute lung injury by promoting apoptosis of type Ⅱ alveolar epithelial cells via the STAT3/miR-21-5p axis ［J］. Mol Immunol ， 2023 ， 163 ： 207 - 215 . DOI： 10.1016/j.molimm.2023.09.016 http://dx.doi.org/10.1016/j.molimm.2023.09.016 .

YUAN P ， CAO Y L ， REN Y C ， et al . AECII-derived miR-21a-5p exosomes alleviate HALI via targeting and regulating PGAM5-mediated necroptosis ［J］. Cell Signal ， 2025 ， 130 ： 111677 . DOI： 10.1016/j.cellsig.2025.111677 http://dx.doi.org/10.1016/j.cellsig.2025.111677 .

FORCINA G C ， DIXON S J . GPX4 at the crossroads of lipid homeostasis and ferroptosis ［J］. Proteomics ， 2019 ， 19 （ 18 ）： e1800311 . DOI： 10.1002/pmic.201800311 http://dx.doi.org/10.1002/pmic.201800311 .

QIN S ， WANG X Q ， REN Y C ， et al . Investigation on the signaling pathways in the mechanism of hyperoxia-induced acute lung injury based on transcriptomics sequencing ［J］. Chin Crit Care Med ， 2024 ， 36 （ 1 ）： 33 - 39 . DOI： 10.3760/cma.j.cn121430-20230411-00262 http://dx.doi.org/10.3760/cma.j.cn121430-20230411-00262 .

OZDEMIR R ， DEMIRTAS G ， PARLAKPINAR H ， et al . Dexpanthenol therapy reduces lung damage in a hyperoxic lung injury in neonatal rats ［J］. J Matern Fetal Neonatal Med ， 2016 ， 29 （ 11 ）： 1801 - 1807 . DOI： 10.3109/14767058.2015.1064104 http://dx.doi.org/10.3109/14767058.2015.1064104 .

HE S Q ， ZHUO Y Z ， CUI L Z ， et al . Naringin dihydrochalcone alleviates sepsis-induced acute lung injury via improving gut microbial homeostasis and activating GPR18 receptor ［J］. Int Immunopharmacol ， 2024 ， 137 ： 112418 . DOI： 10.1016/j.intimp.2024.112418 http://dx.doi.org/10.1016/j.intimp.2024.112418 .

WU S ， HE Y ， LI J ， et al . TREM2 alleviates sepsis-induced acute lung injury by attenuating ferroptosis via the SHP1/STAT3 pathway ［J］. Free Radic Biol Med ， 2025 ， 229 ： 111 - 126 . DOI： 10.1016/j.freeradbiomed.2025.01.022 http://dx.doi.org/10.1016/j.freeradbiomed.2025.01.022 .

XU Z B ， LI J Y ， ZHOU K L ， et al . Exocarpium Citri Grandis ameliorates LPS-induced acute lung injury by suppressing inflammation， NLRP3 inflammasome， and ferroptosis ［J］. J Ethnopharmacol ， 2024 ， 329 ： 118162 . DOI： 10.1016/j.jep.2024.118162 http://dx.doi.org/10.1016/j.jep.2024.118162 .

WU Y C ， PI D J ， ZHOU S Y ， et al . Ginsenoside Rh3 induces pyroptosis and ferroptosis through the Stat3/p53/NRF2 axis in colorectal cancer cells ［J］. Acta Biochim Biophys Sin ， 2023 ， 55 （ 4 ）： 587 - 600 . DOI： 10.3724/abbs.2023068 http://dx.doi.org/10.3724/abbs.2023068 .

HUANG Y H ， CHEN M H ， GUO Q L ， et al . Interleukin-10 induces senescence of activated hepatic stellate cells via STAT3-p53 pathway to attenuate liver fibrosis ［J］. Cell Signal ， 2020 ， 66 ： 109445 . DOI： 10.1016/j.cellsig. 2019. 109445 http://dx.doi.org/10.1016/j.cellsig.2019.109445 .

PROSDOCIMI E ， CARPANESE V ， TODESCA L M ， et al . BioID-based intact cell interactome of the Kv1.3 potassium channel identifies a Kv1.3-STAT3-p53 cellular signaling pathway ［J］. Sci Adv ， 2024 ， 10 （ 36 ）： eadn9361 . DOI： 10.1126/sciadv.adn9361 http://dx.doi.org/10.1126/sciadv.adn9361 .

YANG Y J ， MA Y ， LI Q M ， et al . STAT6 inhibits ferroptosis and alleviates acute lung injury via regulating P53/SLC7A11 pathway ［J］. Cell Death Dis ， 2022 ， 13 （ 6 ）： 530 . DOI： 10.1038/s41419-022-04971-x http://dx.doi.org/10.1038/s41419-022-04971-x .

Views

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

GenX induces cochlear hair cell injury via System Xc⁻-Gpx4-Fsp1 ferroptosis axis

PCBP1-mediated regulation of iron homeostasis suppresses ferroptosis against cadmium-induced neurotoxicity in mouse neuroblastoma cells

Chronic exposure to polystyrene microplastics induces ferroptosis in testicular Sertoli cells

Remimazolam attenuates intestinal ischemia-reperfusion injury in mice by regulating ferroptosis through CX43

Olfactory mucosal mesenchymal stem cells inhibit ferroptosis and attenuate cerebral ischemia-reperfusion injury by up-regulating GPX4

Related Author

LIANG Zhengwei

HONG Huihui

YUAN Wei

JIE Sheng

TIAN Rui

QU Yuchen

TIAN Li

XIE Jia

Related Institution

Neuro-Intelligence Center Laboratory， Chongqing University School of Medicine

Department of Otolaryngology-Head and Neck Surgery， Chongqing General Hospital （Chongqing University Affiliated People’s Hospital）

Department of Otolaryngology-Head and Neck Surgery， the Affiliated Hospital of Southwest Medical University

Department of Occupational Health， Key Laboratory of Electromagnetic Radiation Protection of Ministry of Education， Faculty of Military Preventive Medicine， Army Medical University （Third Military Medical University）

International Joint Research Laboratory of Reproduction and Development of Ministry of Education， School of Public Health， Chongqing Medical University

⁰