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lncRNA ZFAS1介导椎间盘退变中髓核细胞焦亡的机制

Mechanism of lncRNA ZFAS1 mediating nucleus pulposus cell pyroptosis in intervertebral disc degeneration.

作者信息

Fu Yuchun, Zhu Leilei, Ma Bingxu

机构信息

Bengbu Medical University, 2600 Donghai Avenue, Bengbu, Anhui Province, 233000, China.

Physical Examination Center of the First Affiliated Hospital of Bengbu Medical University, Bengbu, 233004, China.

出版信息

J Orthop Surg Res. 2025 Feb 25;20(1):198. doi: 10.1186/s13018-025-05471-2.

DOI:10.1186/s13018-025-05471-2
PMID:40001262
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11863448/
Abstract

BACKGROUND

This study investigates the mechanism of lncRNA ZFAS1 in pyroptosis of TNF-α-induced nucleus pulposus cells (NPCs) in intervertebral disc degeneration (IDD).

METHODS

Mouse NPCs were isolated and induced by TNF-α to establish a cell model of IDD. The cell viability was evaluated by MTT assay. NLRP3, GSDMD-N, and cleaved-Caspase1 expressions were detected by Western blot. IL-1β and IL-18 contents were detected by ELISA. RT-qPCR was performed to determine ZFAS1, miR-155-3p, and METTL14 expressions. After intervening in ZFAS1 expression, the effect of ZFAS1 on pyroptosis was verified by Western blot and ELISA assays. RNA pull down or dual luciferase assay verified the binding between ZFAS1, miR-155-3p, and METTL14.

RESULTS

TNF-α induced pyroptosis of NPCs and promoted ZFAS1 expression. Silence of ZFAS1 repressed pyroptosis of TNF-α-induced NPCs. Mechanistically, ZFAS1 upregulated the transcription of METTL14 by competitively binding to miR-155-3p, thus enhancing NLRP3/Caspase-1-mediated NPC pyroptosis. Inhibition of miR-155-3p or overexpression of METTL14 alleviated the inhibitory effect of ZFAS1 silencing on TNF-α-treated NPC pyroptosis.

CONCLUSION

ZFAS1 facilitates NLRP3/Caspase-1-mediated pyroptosis of NPCs in IDD via miR-155-3p/METTL14 axis.

摘要

背景

本研究探讨长链非编码RNA ZFAS1在椎间盘退变（IDD）中肿瘤坏死因子-α（TNF-α）诱导的髓核细胞（NPCs）焦亡中的作用机制。

方法

分离小鼠NPCs并用TNF-α诱导，建立IDD细胞模型。采用MTT法评估细胞活力。通过蛋白质免疫印迹法检测NLRP3、GSDMD-N和裂解的Caspase1的表达。采用酶联免疫吸附测定法检测白细胞介素-1β（IL-1β）和白细胞介素-18（IL-18）含量。通过逆转录-定量聚合酶链反应（RT-qPCR）检测ZFAS1、微小RNA-155-3p（miR-155-3p）和甲基转移酶样14（METTL14）的表达。干预ZFAS1表达后，通过蛋白质免疫印迹法和酶联免疫吸附测定法验证ZFAS1对焦亡的影响。RNA下拉实验或双荧光素酶报告基因检测验证ZFAS1、miR-155-3p和METTL14之间的结合。

结果

TNF-α诱导NPCs焦亡并促进ZFAS1表达。沉默ZFAS1可抑制TNF-α诱导的NPCs焦亡。机制上，ZFAS1通过竞争性结合miR-155-3p上调METTL14的转录，从而增强NLRP3/半胱天冬酶-1介导的NPCs焦亡。抑制miR-155-3p或过表达METTL14可减轻ZFAS1沉默对TNF-α处理的NPCs焦亡的抑制作用。

结论

ZFAS1通过miR-155-3p/METTL14轴促进IDD中NPCs的NLRP3/半胱天冬酶-1介导的焦亡。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2672/11863448/2b705d6fcd07/13018_2025_5471_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2672/11863448/14c2688d9b43/13018_2025_5471_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2672/11863448/660a8eb6393c/13018_2025_5471_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2672/11863448/21047b797bb8/13018_2025_5471_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2672/11863448/df10d5027cf4/13018_2025_5471_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2672/11863448/2b705d6fcd07/13018_2025_5471_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2672/11863448/14c2688d9b43/13018_2025_5471_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2672/11863448/660a8eb6393c/13018_2025_5471_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2672/11863448/21047b797bb8/13018_2025_5471_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2672/11863448/df10d5027cf4/13018_2025_5471_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2672/11863448/2b705d6fcd07/13018_2025_5471_Fig5_HTML.jpg

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