Ferulic acid/GRB2/NF-κB signaling pathway that alleviates ferroptosis-induced apoptosis of nucleus pulposus cells is a potential mechanism for intervertebral disc degeneration

IF 1.5 Q3 ORTHOPEDICS

Journal of orthopaedics Pub Date : 2025-06-21 DOI:10.1016/j.jor.2025.06.013

Minde Li , Xinya Liu

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引用次数: 0

Abstract

Background

Intervertebral disc degeneration (IDD) is one of the main causes of low back pain, and its pathogenesis involves the gradual loss of nucleus pulposus cells (NPCs). However, the molecular mechanisms linking these pathways are not yet fully understood.

Objective

This study aims to investigate the role of ferulic acid (FA) in IDD and its potential mechanisms of action, providing potential therapeutic targets for IDD.

Methods

Analysis of 10 common traditional Chinese medicine prescriptions for lumbar disc herniation revealed that ferulic acid (Ferulic acid, FA) is a major active pharmaceutical ingredient. CCK8 confirmed that FA promotes the proliferation of NP cells. Edu results showed that FA promotes NP cell proliferation, while ferroptosis inhibits NP proliferation. Moreover, FA can alleviate the inhibitory effect of ferroptosis on NP cell proliferation. Subsequently, animal experiments confirmed that FA alleviates IDD in rats, and safranin O-fast green staining results confirmed that FA has a role in alleviating IDD lesions. Analysis of the GSE15227 and GSE23130 datasets showed that GRB2 is a hub gene in the progression of IDD, and molecular docking results showed that FA can bind to GRB2. WB demonstrated that FA significantly increased the expression of IκBα in ferroptosis-induced NP cells, thereby promoting proliferation. Meanwhile, the addition of the NF-κB agonist (TNF-α) significantly reduced IκBα expression and significantly inhibited NP cell proliferation.

Results

FA significantly inhibited ferroptosis markers and NPC proliferation in NPCs. GRB2 is one of the hub genes of IDD, and molecular docking results showed that FA has binding sites with GRB2. Meanwhile, FA upregulated IκBα, inhibiting the nuclear translocation of NF-κB and its downstream pro-inflammatory cytokines.

Conclusion

FA can significantly alleviate the progression of IDD. FA may inhibit NPC inflammation and lipid peroxidation through the GRB2/NF-κB pathway, The FA-GRB2/NF-κB axis is a potential therapeutic target for intervertebral disc degeneration.

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阿魏酸/GRB2/NF-κB信号通路缓解铁致髓核细胞凋亡是椎间盘退变的潜在机制

背景椎间盘退变（IDD）是腰痛的主要原因之一，其发病机制涉及髓核细胞（NPCs）的逐渐丧失。然而，连接这些途径的分子机制尚不完全清楚。目的探讨阿魏酸（FA）在IDD中的作用及其可能的作用机制，为IDD提供潜在的治疗靶点。方法对治疗腰椎间盘突出症的10种常用中药处方进行分析，发现阿魏酸（ferulic acid， FA）是其主要有效成分。CCK8证实FA促进NP细胞的增殖。Edu结果显示，FA促进NP细胞增殖，而铁下垂抑制NP细胞增殖。此外，FA可减轻铁下垂对NP细胞增殖的抑制作用。随后，动物实验证实FA可减轻大鼠的IDD，橘红素O-fast绿色染色结果证实FA具有减轻IDD病变的作用。对GSE15227和GSE23130数据集的分析表明，GRB2是IDD进展中的枢纽基因，分子对接结果表明，FA可以与GRB2结合。WB结果表明，FA可显著提高铁中毒诱导的NP细胞中i - κ b α的表达，从而促进细胞增殖。同时，NF-κB激动剂（TNF-α）的加入可显著降低i -κB α的表达，显著抑制NP细胞的增殖。结果fa能明显抑制铁下垂标志物，抑制NPC细胞增殖。GRB2是IDD的枢纽基因之一，分子对接结果表明，FA与GRB2有结合位点。同时，FA上调i -κB α，抑制NF-κB及其下游促炎细胞因子的核易位。结论fa能明显缓解IDD的进展。FA可能通过GRB2/NF-κB途径抑制鼻咽癌炎症和脂质过氧化，FA-GRB2/NF-κB轴是椎间盘退变的潜在治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of orthopaedics ORTHOPEDICS-

CiteScore

3.50

自引率

6.70%

发文量

202

审稿时长

56 days

期刊介绍： Journal of Orthopaedics aims to be a leading journal in orthopaedics and contribute towards the improvement of quality of orthopedic health care. The journal publishes original research work and review articles related to different aspects of orthopaedics including Arthroplasty, Arthroscopy, Sports Medicine, Trauma, Spine and Spinal deformities, Pediatric orthopaedics, limb reconstruction procedures, hand surgery, and orthopaedic oncology. It also publishes articles on continuing education, health-related information, case reports and letters to the editor. It is requested to note that the journal has an international readership and all submissions should be aimed at specifying something about the setting in which the work was conducted. Authors must also provide any specific reasons for the research and also provide an elaborate description of the results.