Targeting Ferroptosis Holds Potential for Intervertebral Disc Degeneration Therapy

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.

Keywords: ferroptosis; intervertebral disc degeneration; iron; lipid peroxidation; treatment.

Figure 1

The potential ferroptosis-related pathways in nucleus pulposus cells. AA, arachidonic acid; ATF3, activation transcription factor 3; BMSC, bone marrow mesenchymal stem cell; DMT1, divalent metal transporter 1; DNMT3, DNA methyltransferase 3; EVs, extracellular vesicles; FTH1, ferritin heavy chain 1; FPN, ferroportin; GPX4, glutathione peroxidase 4; GSH, glutathione; HCP1, heme carrier protein 1; Hcy, homocysteine; HO-1, heme oxygenase-1; JNK, c-jun N-terminal kinase; LC3, microtubule-associated protein light chain 3; Met, methionine; MTF1, metal-regulatory transcription factor 1; NCOA4, nuclear receptor coactivator 4; NRF2, nuclear factor E2-related factor 2; ROS, reactive oxygen species; SLC7A11, cystine/glutamate antiporter; TBHP, tert-butyl hydroperoxide; TCA, tricarboxylic acid; TfR1, transferrin receptor 1.

Figure 2

The potential ferroptosis-related pathways in annulus fibrosus cells (left) and endplate chondrocytes (right). DMT1, divalent metal transporter 1; FTH1, ferritin heavy chain 1; FPN, ferroportin; GPX4, glutathione peroxidase 4; GSH, glutathione; IL-6, interleukin-6; IL-6R, interleukin-6 receptor; LC3, microtubule-associated protein light chain 3; NCOA4, nuclear receptor coactivator 4; ROS, reactive oxygen species; SLC7A11, cystine/glutamate antiporter; TBHP, tert-butyl hydroperoxide; TfR1, transferrin receptor 1.