铁死亡介导椎间盘退变的研究进展

doi:10.13418/j.issn.1001-165x.2025.1.16

摘要/Abstract

摘要： 椎间盘退变（intervertebral disc degeneration，IVDD）是脊柱外科常见的病变，常常导致椎管狭窄、椎间盘突出等脊柱退行性疾病，随着年龄的增长，其患病率呈上升趋势。IVDD的发病机制复杂，尚不明确，目前仍无有效治疗药物。铁死亡是一种新型的细胞死亡形式，其特点是铁依赖性的脂质过氧化物的积累，在许多疾病的发展中具有重要作用。近年研究发现，铁死亡与IVDD的发生、发展密切相关，但其在IVDD中的作用机制尚未完全明确。本文现就铁死亡的分子机制、铁死亡与IVDD的关系及其在临床应用潜力方面作一综述，旨在为IVDD的预防及治疗提供新思路。

关键词: 铁死亡, , , 椎间盘退变, , , 氧化应激, , , 谷胱甘肽过氧化物酶4

Abstract: Intervertebral disc degeneration (IVDD) is a common lesion in spinal surgery, which often leads to spinal degenerative diseases such as spinal stenosis and disc herniation. As age increases, its prevalence is on the rise. The pathogenesis of IVDD is complex and unclear, and there are currently no effective treatments. Ferroptosis is a novel form of cell death characterized by the accumulation of iron-dependent lipid peroxides and plays an important role in the development of many diseases. Recent studies have found that ferroptosis is closely related to the occurrence and development of IVDD, but its mechanism of action in IVDD has not yet been fully understood. This article reviewed the molecular mechanism of ferroptosis, the relationship between ferroptosis and IVDD, and its clinical application potential, aiming to provide new ideas for the prevention and treatment of IVDD.

Key words: Ferroptosis, , , Intervertebral disc degeneration, , , Oxidative stress, , , GPX4

中图分类号:

R681.53

邓棕元, 陈崇, 梁国彦, 叶勇裕, 余正然, 余涛, 汪露通, 梁昌详, 昌耘冰. 铁死亡介导椎间盘退变的研究进展[J]. 中国临床解剖学杂志, 2025, 43(1): 102-106.

Deng Zongyuan, Chen Chong, Liang Guoyan, Ye Yongyu, Yu Zhengran, Yu Tao, Wang Lutong, Liang Changxiang, Chang Yunbing. Research progress on ferroptosis-mediated intervertebral disc degeneration[J]. Chinese Journal of Clinical Anatomy, 2025, 43(1): 102-106.

参考文献

[1] Knezevic NN, Candido KD, Vlaeyen JWS, et al. Low back pain[J]. Lancet (London, England), 2021, 398(10294): 78-92. DOl: 10.1016/s0140-6736(21)00733-9.
[2] Wu PH, Kim HS, Jang IT. Intervertebral disc diseases PART 2: A review of the current diagnostic and treatment strategies for intervertebral disc disease[J]. Int J Mol Sci, 2020, 21(6)2135. DOl: 10.3390/ijms21062135.
[3] Ru Q, Li Y, Xie W, et al. Fighting age-related orthopedic diseases: focusing on ferroptosis[J]. Bone Res, 2023, 11(1): 12. DOl: 10.1038/s41413-023-00247-y.
[4] Wong J, Sampson SL, Bell-Briones H, et al. Nutrient supply and nucleus pulposus cell function: effects of the transport properties of the cartilage endplate and potential implications for intradiscal biologic therapy[J]. Osteoarthritis Cartilage, 2019, 27(6): 956-964. DOl: 10.1016/j.joca.2019.01.013.
[5] Zou X, Zhang X, Han S, et al. Pathogenesis and therapeutic implications of matrix metalloproteinases in intervertebral disc degeneration: A comprehensive review[J]. Biochimie, 2023, 214(Pt B): 27-48. DOl: https://doi.org/10.1016/j.biochi.2023.05.015.
[6] Boos N, Weissbach S, Rohrbach H, et al. Classification of age-related changes in lumbar intervertebral discs: 2002 Volvo Award in basic science[J]. Spine (Phila Pa 1976), 2002, 27(23): 2631-2644. DOl: 10.1097/00007632-200212010-00002.
[7] Mohd Isa IL, Teoh SL, Mohd Nor NH, et al. Discogenic low back pain: anatomy, pathophysiology and treatments of intervertebral disc degeneration[J]. Int J Mol Sci, 2022, 24(1):208. DOl: 10.3390/ijms24010208.
[8] Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death[J]. Cell, 2012, 149(5): 1060-1072. DOl: 10.1016/j.cell.2012.03.042.
[9] Stockwell BR. Ferroptosis turns 10: Emerging mechanisms, physiolo gical functions, and therapeutic applications[J]. Cell, 2022, 185(14): 2401-2421. DOl: 10.1016/j.cell.2022.06.003.
[10]Stoyanovsky DA, Tyurina YY, Shrivastava I, et al. Iron catalysis of lipid peroxidation in ferroptosis: Regulated enzymatic or random free radical reaction [J] ? Free Radic Biol Med, 2019, 133: 153-161. DOl: 10.1016/j.freeradbiomed.2018.09.008.
[11]Koppula P, Zhang Y, Zhuang L, et al. Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer[J]. Cancer Commun (London, England), 2018, 38(1): 12. DOl: 10.1186/s40880-018-0288-x.
[12]Zheng J, Conrad M. The metabolic underpinnings of ferroptosis[J]. Cell Metab, 2020, 32(6): 920-937. DOl: 10.1016/j.cmet.2020.10.011.
[13]Zhang Y, Han S, Kong M, et al. Single-cell RNA-seq analysis identifies unique chondrocyte subsets and reveals involvement of ferroptosis in human intervertebral disc degeneration[J]. Osteoarthritis Cartilage, 2021, 29(9): 1324-1334. DOl: 10.1016/j.joca.2021.06.010.
[14]Shan L, Xu X, Zhang J, et al. Increased hemoglobin and heme in MALDI-TOF MS analysis induce ferroptosis and promote degeneration of herniated human nucleus pulposus[J]. Molecular medicine (Cambridge, Mass), 2021, 27(1): 103. DOl: 10.1186/s10020-021-00368-2.
[15]Lu S, Song Y, Luo R, et al. Ferroportin-dependent iron homeostasis protects against oxidative stress-induced nucleus pulposus cell ferroptosis and ameliorates intervertebral disc degeneration in vivo[J]. Oxid Med Cell Longev, 2021, 2021: 6670497. DOl: 10.1155/2021/6670497.
[16]Wang W, Jing X, Du T, et al. Iron overload promotes intervertebral disc degeneration via inducing oxidative stress and ferroptosis in endplate chondrocytes[J]. Free Radic Biol Med, 2022, 190: 234-246. DOl: 10.1016/j.freeradbiomed.2022.08.018.
[17]Zhang X, Chen J, Huang B, et al. Obesity mediates apoptosis and extracellular matrix metabolic imbalances via MAPK pathway activation in intervertebral disk degeneration[J]. Front Physiol, 2019, 10: 1284. DOl: 10.3389/fphys.2019.01284.
[18]Yang S, Lian G. ROS and diseases: role in metabolism and energy supply[J]. Mol Cell Biochem, 2020, 467(1-2): 1-12. DOl: 10.1007/s11010-019-03667-9.
[19]Jin LY, Lv ZD, Wang K, et al. Estradiol alleviates intervertebral disc degeneration through modulating the antioxidant enzymes and inhibiting autophagy in the model of menopause rats[J]. Oxid Med Cell Longev, 2018, 2018: 7890291. DOl: 10.1155/2018/7890291.
[20]Zhang X, Huang Z, Xie Z, et al. Homocysteine induces oxidative stress and ferroptosis of nucleus pulposus via enhancing methylation of GPX4[J]. Free Radic Biol Med, 2020, 160: 552-565. DOl: 10.1016/j.freeradbiomed. 2020. 08. 029.
[21]张旭阳. 高同型半胱氨酸促进GPX4甲基化介导髓核氧化/还原失衡在腰椎间盘退变中的作用机制研究[D]. 浙江大学, 2021.
[22]Yurube T, Takeoka Y, Kanda Y, et al. Intervertebral disc cell fate during aging and degeneration: apoptosis, senescence, and autophagy[J]. N Am Spine Soc J, 2023, 14: 100210. DOl: 10.1016/j.xnsj.2023.100210.
[23]Kakiuchi Y, Yurube T, Kakutani K, et al. Pharmacological inhibition of mTORC1 but not mTORC2 protects against human disc cellular apoptosis, senescence, and extracellular matrix catabolism through Akt and autophagy induction[J]. Osteoarthritis Cartilage, 2019, 27(6): 965-976. DOl: 10.1016/j.joca.2019.01.009.
[24]Wu X, Song Y, Li S, et al. Pramlintide regulation of extracellular matrix (ECM) and apoptosis through mitochondrial-dependent pathways in human nucleus pulposus cells[J]. Int J Immunopathol Pharmacol, 2018, 31: 394632017747500. DOl: 10.1177/0394632017747500.
[25]Li S, Liao Z, Yin H, et al. G3BP1 coordinates lysophagy activity to protect against compression-induced cell ferroptosis during intervertebral disc degeneration[J]. Cell Prolif, 2023, 56(3): e13368. DOl: 10.1111/cpr.13368.
[26]Conlon M, Poltorack CD, Forcina GC, et al. A compendium of kinetic modulatory profiles identifies ferroptosis regulators[J]. Nat Chem Biol, 2021, 17(6): 665-674. DOl: 10.1038/s41589-021-00751-4.
[27]Baird L, Yamamoto M. The molecular mechanisms regulating the KEAP1-NRF2 pathway[J]. Mol Cell Biol, 2020, 40(13). DOl: 10.1128/mcb.00099-20.
[28]Luo X, Huan L, Lin F, et al. Ulinastatin ameliorates IL-1β-induced cell dysfunction in human nucleus pulposus cells via Nrf2/NF-κB pathway[J]. Oxid Med Cell Longev, 2021, 2021: 5558687. DOl: 10.1155/2021/5558687.
[29]Wang R, Luo D, Li Z, et al. Dimethyl fumarate ameliorates nucleus pulposus cell dysfunction through activating the Nrf2/HO-1 pathway in intervertebral disc degeneration[J]. Comput Math Methods Med, 2021, 2021: 6021763. DOl: 10.1155/2021/6021763.
[30]Bai X, Lian Y, Hu C, et al. Cyanidin-3-glucoside protects against high glucose-induced injury in human nucleus pulposus cells by regulating the Nrf2/HO-1 signaling[J]. J Appl Toxicol, 2022, 42(7): 1137-1145. DOl: 10.1002/jat.4281.
[31]Zuo R, Wang Y, Li J, et al. Rapamycin induced autophagy inhibits inflammation-mediated endplate degeneration by enhancing Nrf2/Keap1 signaling of cartilage endplate stem cells[J]. Stem Cells (Dayton, Ohio), 2019, 37(6): 828-840. DOl: 10.1002/stem.2999.
[32]Di Maggio R, Maggio A. The new era of chelation treatments: effectiveness and safety of 10 different regimens for controlling iron overloading in thalassaemia major[J]. Br J Haematol, 2017, 178(5): 676-688. DOl: 10.1111/bjh.14712.
[33]Yang RZ, Xu WN, Zheng HL, et al. Involvement of oxidative stress-induced annulus fibrosus cell and nucleus pulposus cell ferroptosis in intervertebral disc degeneration pathogenesis[J]. J Cell Physiol, 2021, 236(4): 2725-2739. DOl: 10.1002/jcp.30039.
[34]Xi J, Zhang Z, Wang Z, et al. Hinokitiol functions as a ferroptosis inhibitor to confer neuroprotection[J]. Free Radic Biol Med, 2022, 190: 202-215. DOl: 10.1016/j.freeradbiomed.2022.08.011.
[35]Chen Y, Cao X, Pan B, et al. Verapamil attenuates intervertebral disc degeneration by suppressing ROS overproduction and pyroptosis via targeting the Nrf2/TXNIP/NLRP3 axis in four-week puncture-induced rat models both in vivo and in vitro[J]. Int Immunopharmacol, 2023, 123: 110789. DOl: 10.1016/j.intimp.2023.110789.
[36]Yang G, Liu X, Jing X, et al. Astaxanthin suppresses oxidative stress and calcification in vertebral cartilage endplate via activating Nrf-2/HO-1 signaling pathway[J]. Int Immunopharmacol, 2023, 119: 110159. DOl: 10.1016/j.intimp.2023.110159.