Targeting Ferroptosis Holds Potential for Intervertebral Disc Degeneration Therapy

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2022 Nov 11

PMID 36359904

Authors

Jiaxing Chen

Xinyu Yang

Yi Feng

Qiaochu Li

Jingjin Ma

Linbang Wang

Zhengxue Quan

Affiliations

Soon will be listed here.

Abstract

Intervertebral disc degeneration (IVDD) is a common pathological condition responsible for lower back pain, which can significantly increase economic and social burdens. Although considerable efforts have been made to identify potential mechanisms of disc degeneration, the treatment of IVDD is not satisfactory. Ferroptosis, a recently reported form of regulated cell death (RCD), is characterized by iron-dependent lipid peroxidation and has been demonstrated to be responsible for a variety of degenerative diseases. Accumulating evidence suggests that ferroptosis is implicated in IVDD by decreasing viability and increasing extracellular matrix degradation of nucleus pulposus cells, annulus fibrosus cells, or endplate chondrocytes. In this review, we summarize the literature regarding ferroptosis of intervertebral disc cells and discuss its molecular pathways and biomarkers for treating IVDD. Importantly, ferroptosis is verified as a promising therapeutic target for IVDD.

Citing Articles

Gallic acid protects intervertebral disc cells from ferroptosis and alleviates intervertebral disc degeneration by regulating key factors of oxidative stress.

Zhu Z, Huang Z, Zhang C, Xu B, Chen H, Pei S Front Pharmacol. 2025; 16:1501725.

PMID: 39963245 PMC: 11830718. DOI: 10.3389/fphar.2025.1501725.

Humanin reduces nucleus pulposus cells ferroptosis to alleviate intervertebral disc degeneration: An in vitro and in vivo study.

Zhu D, Wang Z, Li Y, Chen S, Kang X J Orthop Translat. 2025; 50:274-294.

PMID: 39902261 PMC: 11788685. DOI: 10.1016/j.jot.2024.12.002.

Role of macrophage in intervertebral disc degeneration.

Dou Y, Zhang Y, Liu Y, Sun X, Liu X, Li B Bone Res. 2025; 13(1):15.

PMID: 39848963 PMC: 11758090. DOI: 10.1038/s41413-024-00397-7.

MUC1 and CREB3 are Hub Ferroptosis Suppressors for Nucleus Pulposus and Annulus Fibrosus Degeneration by Integrated Bioinformatics and Experimental Verification.

Yang X, Li Q, Wang L, Chen J, Quan Z J Inflamm Res. 2024; 17:8965-8984.

PMID: 39583856 PMC: 11584408. DOI: 10.2147/JIR.S489052.

Application trends and strategies of hydrogel delivery systems in intervertebral disc degeneration: A bibliometric review.

Wang J, Zhang Y, Huang Y, Hao Z, Shi G, Guo L Mater Today Bio. 2024; 28:101251.

PMID: 39318370 PMC: 11421353. DOI: 10.1016/j.mtbio.2024.101251.

References

Yang R, Xu W, Zheng H, Zheng X, Li B, Jiang L . Involvement of oxidative stress-induced annulus fibrosus cell and nucleus pulposus cell ferroptosis in intervertebral disc degeneration pathogenesis. J Cell Physiol. 2020; 236(4):2725-2739. PMC: 7891651. DOI: 10.1002/jcp.30039. View

Xu W, Yang R, Zheng H, Yu W, Zheng X, Li B . PGC-1α acts as an mediator of Sirtuin2 to protect annulus fibrosus from apoptosis induced by oxidative stress through restraining mitophagy. Int J Biol Macromol. 2019; 136:1007-1017. DOI: 10.1016/j.ijbiomac.2019.06.163. View

Krut Z, Pelled G, Gazit D, Gazit Z . Stem Cells and Exosomes: New Therapies for Intervertebral Disc Degeneration. Cells. 2021; 10(9). PMC: 8471333. DOI: 10.3390/cells10092241. View

Risbud M, Shapiro I . Role of cytokines in intervertebral disc degeneration: pain and disc content. Nat Rev Rheumatol. 2013; 10(1):44-56. PMC: 4151534. DOI: 10.1038/nrrheum.2013.160. View

Zhang X, Huang Z, Xie Z, Chen Y, Zheng Z, Wei X . Homocysteine induces oxidative stress and ferroptosis of nucleus pulposus via enhancing methylation of GPX4. Free Radic Biol Med. 2020; 160:552-565. DOI: 10.1016/j.freeradbiomed.2020.08.029. View

Dixon S, Lemberg K, Lamprecht M, Skouta R, Zaitsev E, Gleason C . Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012; 149(5):1060-72. PMC: 3367386. DOI: 10.1016/j.cell.2012.03.042. View

Masaldan S, Bush A, Devos D, Rolland A, Moreau C . Striking while the iron is hot: Iron metabolism and ferroptosis in neurodegeneration. Free Radic Biol Med. 2018; 133:221-233. DOI: 10.1016/j.freeradbiomed.2018.09.033. View

Ashinsky B, Bonnevie E, Mandalapu S, Pickup S, Wang C, Han L . Intervertebral Disc Degeneration Is Associated With Aberrant Endplate Remodeling and Reduced Small Molecule Transport. J Bone Miner Res. 2020; 35(8):1572-1581. PMC: 8207249. DOI: 10.1002/jbmr.4009. View

Santana-Codina N, Gikandi A, Mancias J . The Role of NCOA4-Mediated Ferritinophagy in Ferroptosis. Adv Exp Med Biol. 2021; 1301:41-57. DOI: 10.1007/978-3-030-62026-4_4. View

10.

Ursini F, Maiorino M . Lipid peroxidation and ferroptosis: The role of GSH and GPx4. Free Radic Biol Med. 2020; 152:175-185. DOI: 10.1016/j.freeradbiomed.2020.02.027. View

11.

Wang W, Jing X, Du T, Ren J, Liu X, Chen F . Iron overload promotes intervertebral disc degeneration via inducing oxidative stress and ferroptosis in endplate chondrocytes. Free Radic Biol Med. 2022; 190:234-246. DOI: 10.1016/j.freeradbiomed.2022.08.018. View

12.

Harada N, Kanayama M, Maruyama A, Yoshida A, Tazumi K, Hosoya T . Nrf2 regulates ferroportin 1-mediated iron efflux and counteracts lipopolysaccharide-induced ferroportin 1 mRNA suppression in macrophages. Arch Biochem Biophys. 2011; 508(1):101-9. DOI: 10.1016/j.abb.2011.02.001. View

13.

Zhou X, Chen L, Grad S, Alini M, Pan H, Yang D . The roles and perspectives of microRNAs as biomarkers for intervertebral disc degeneration. J Tissue Eng Regen Med. 2017; 11(12):3481-3487. DOI: 10.1002/term.2261. View

14.

Protchenko O, Baratz E, Jadhav S, Li F, Shakoury-Elizeh M, Gavrilova O . Iron Chaperone Poly rC Binding Protein 1 Protects Mouse Liver From Lipid Peroxidation and Steatosis. Hepatology. 2020; 73(3):1176-1193. PMC: 8364740. DOI: 10.1002/hep.31328. View

15.

Wei Q, Liu D, Chu G, Yu Q, Liu Z, Li J . TGF-β1-supplemented decellularized annulus fibrosus matrix hydrogels promote annulus fibrosus repair. Bioact Mater. 2022; 19:581-593. PMC: 9108517. DOI: 10.1016/j.bioactmat.2022.04.025. View

16.

Zhang C, Wang B, Zhao X, Li X, Lou Z, Chen X . Iron deficiency accelerates intervertebral disc degeneration through affecting the stability of DNA polymerase epsilon complex. Am J Transl Res. 2019; 10(11):3430-3442. PMC: 6291718. View

17.

Ma S, Henson E, Chen Y, Gibson S . Ferroptosis is induced following siramesine and lapatinib treatment of breast cancer cells. Cell Death Dis. 2016; 7:e2307. PMC: 4973350. DOI: 10.1038/cddis.2016.208. View

18.

Shen M, Li Y, Wang Y, Shao J, Zhang F, Yin G . N-methyladenosine modification regulates ferroptosis through autophagy signaling pathway in hepatic stellate cells. Redox Biol. 2021; 47:102151. PMC: 8495178. DOI: 10.1016/j.redox.2021.102151. View

19.

Liu J, Kang R, Tang D . Signaling pathways and defense mechanisms of ferroptosis. FEBS J. 2021; 289(22):7038-7050. DOI: 10.1111/febs.16059. View

20.

Dowdell J, Erwin M, Choma T, Vaccaro A, Iatridis J, Cho S . Intervertebral Disk Degeneration and Repair. Neurosurgery. 2017; 80(3S):S46-S54. PMC: 5585783. DOI: 10.1093/neuros/nyw078. View