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GATA6通过靶向TLR2/AKR1C3调控铁死亡促进椎间盘退变进展。

GATA6 Facilitates Progression of Intervertebral Disc Degeneration by Regulating Ferroptosis via Targeting TLR2/AKR1C3.

作者信息

Wang Xiaobo, Wang Bingyu, Shi Jiawei, Chen Zefu, Wu Yongpei, Liu Jingmin, Zhang Zhongmin, Wang Yang, Dan Jia, Zheng Xin

机构信息

Department of Spine Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Department of Spine Surgery, The Affiliated TCM Hospital of Guangzhou Medical University, Guangzhou, Guangzhou, China.

出版信息

Int J Biol Sci. 2025 Jan 13;21(3):1174-1186. doi: 10.7150/ijbs.102776. eCollection 2025.

DOI:10.7150/ijbs.102776
PMID:39897029
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11781159/
Abstract

This study explored the role of ferroptosis in intervertebral disc degeneration (IVDD), and identified GATA6 as a key regulator of this process. A ferroptosis-related gene risk coefficient model was constructed using differential gene expression analysis of the GSE70362 dataset. The analysis identified GATA6 as a significant factor in IVDD progression. GATA6 was shown to promote ferroptosis in nucleus pulposus cells (NPCs) by regulating the expression of AKR1C3 through the TLR2 pathway. experiments demonstrated that GATA6 knockdown reduced ferroptosis, improved cell viability, and mitigated extracellular matrix degradation, whereas GATA6 overexpression exacerbated these processes. Furthermore, AKR1C3 was found to be crucial for GATA6-mediated ferroptosis, and modulation of the TLR2-AKR1C3 axis significantly impacted the degeneration of NPCs. These findings suggest that targeting GATA6 and its downstream TLR2-AKR1C3 pathway may provide new therapeutic approaches for IVDD.

摘要

本研究探讨了铁死亡在椎间盘退变（IVDD）中的作用，并确定GATA6是这一过程的关键调节因子。利用GSE70362数据集的差异基因表达分析构建了铁死亡相关基因风险系数模型。分析确定GATA6是IVDD进展中的一个重要因素。研究表明，GATA6通过TLR2途径调节AKR1C3的表达，从而促进髓核细胞（NPCs）的铁死亡。实验证明，敲低GATA6可减少铁死亡，提高细胞活力，并减轻细胞外基质降解，而GATA6过表达则会加剧这些过程。此外，发现AKR1C3对GATA6介导的铁死亡至关重要，调节TLR2-AKR1C3轴会显著影响NPCs的退变。这些发现表明，靶向GATA6及其下游的TLR2-AKR1C3途径可能为IVDD提供新的治疗方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/75d2/11781159/16a140a837f8/ijbsv21p1174g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/75d2/11781159/c938a67012ee/ijbsv21p1174g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/75d2/11781159/0cb1ebce9716/ijbsv21p1174g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/75d2/11781159/2b546a31a741/ijbsv21p1174g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/75d2/11781159/860e0d37c0a9/ijbsv21p1174g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/75d2/11781159/49e31b397060/ijbsv21p1174g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/75d2/11781159/16a140a837f8/ijbsv21p1174g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/75d2/11781159/c938a67012ee/ijbsv21p1174g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/75d2/11781159/0cb1ebce9716/ijbsv21p1174g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/75d2/11781159/2b546a31a741/ijbsv21p1174g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/75d2/11781159/860e0d37c0a9/ijbsv21p1174g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/75d2/11781159/49e31b397060/ijbsv21p1174g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/75d2/11781159/16a140a837f8/ijbsv21p1174g006.jpg

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[1]
GATA6 Facilitates Progression of Intervertebral Disc Degeneration by Regulating Ferroptosis via Targeting TLR2/AKR1C3.

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[3]
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[7]
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[8]
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[9]
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[10]
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本文引用的文献

[1]
Inflammation dynamically regulates steroid hormone metabolism and action within macrophages in rheumatoid arthritis.

J Autoimmun. 2024-7

[2]
Piezo1 channel exaggerates ferroptosis of nucleus pulposus cells by mediating mechanical stress-induced iron influx.

Bone Res. 2024-3-29

[3]
A new perspective on intervertebral disc calcification-from bench to bedside.

Bone Res. 2024-1-22

[4]
Bioinformatics-based discovery of intervertebral disc degeneration biomarkers and immune-inflammatory infiltrates.

JOR Spine. 2023-12-22

[5]
Progress in regulating inflammatory biomaterials for intervertebral disc regeneration.

Bioact Mater. 2023-12-8

[6]
The transcription factor GATA6 accelerates vascular smooth muscle cell senescence-related arterial calcification by counteracting the role of anti-aging factor SIRT6 and impeding DNA damage repair.

Kidney Int. 2024-1

[7]
Mechanisms of inhibition of nucleus pulposus cells pyroptosis through SDF1/CXCR4-NFkB-NLRP3 axis in the treatment of intervertebral disc degeneration by Duhuo Jisheng Decoction.

Int Immunopharmacol. 2023-11

[8]
The role of ferroptosis in intervertebral disc degeneration.

Front Cell Dev Biol. 2023-7-27

[9]
Endothelial Gata6 deletion reduces monocyte recruitment and proinflammatory macrophage formation and attenuates atherosclerosis through Cmpk2-Nlrp3 pathways.

Redox Biol. 2023-8

[10]
The deubiquitinase USP11 ameliorates intervertebral disc degeneration by regulating oxidative stress-induced ferroptosis via deubiquitinating and stabilizing Sirt3.

Redox Biol. 2023-6

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