Intervertebral disc degeneration (IDD), being the predominant root cause of lower back pain, has led to an enormous socioeconomic burden in the world. Ferroptosis is an iron-dependent nonapoptotic and nonpyroptotic programmed cell death associated with an increase in reactive oxygen species (ROS), which has been implicated in the pathogenesis of IDD. Activation transcription factor 3 (ATF3) is widely reported to promote ferroptosis and apoptosis in multiple diseases, but its roles and underlying regulatory mechanism in IDD have not been identified. FAoptosis is defined as a mixed cell death consisting of ferroptosis and apoptosis. The loss- and gain-of-function experiments demonstrated that ATF3 positively regulated tert-butyl hydroperoxide- (TBHP-) induced nucleus pulposus cell (NPC) FAoptosis, ROS production, inflammatory response, and extracellular matrix (ECM) degradation. Furthermore, silencing ATF3 ameliorated the progression of IDD in vivo, whereas its overexpression showed the opposite phenotype. Bioinformatics analysis and molecular experiments corroborated that ATF3 is a direct target of miR-874-3p, suggesting that the upregulation of ATF3 in IDD might be caused at least in part due to the downregulation of miR-874-3p in IDD, thereby relieving the inhibition of ATF3 by miR-874-3p. The findings revealed that ATF3 has the potential to be used as a promising therapeutic target against IDD.

lower back pain (lBP) is one of the predominant factors contributing to dyskinesia and remains a serious social and economic burden worldwide. intervertebral disc degeneration (idd) is the leading cause of lBP; the existing idd treatments cannot completely prevent idd. circular rnas (circrnas) are non-coding rnas resulting from back-splicing with unique structural characteristics and functions. accumulating evidence suggests that circrnas are involved in the pathological process of idd and modulate a range of idd-related genes or proteins. However, the underlying circrna-mediated regulatory mechanisms remain poorly understood. The aim of the present review is to describe the current understanding of circRNA characteristics, classification, biogenesis and function in relation to its specific roles in idd. additionally, the limitations on the current knowledge in the field and the future direction of IDD-related research are also discussed. Contents 1. introduction 2. characteristics 3. Classifications 4. Biogenesis and functions 5. Specific roles of circRNA in IDD 6. current limitations and future directions 7. conclusions

The abnormal function of nucleus pulposus cells (NPCs) plays a crucial role in the pathogenesis of intervertebral disc degeneration (IVDD). Recent studies have demonstrated that circular RNAs (circRNAs) are involved in the pathological process of IVDD by regulating NPCs’ function. Nevertheless, the investigation on circRNA-circRNA interaction has not yet been reported. Here, we identified the top upregulated circ_0040039 and circ_0004354 in IVDD, derived from the syntrophin beta 2 gene but had different degrees of biological functions. Accumulating studies have reported PANoptosis is composed of apoptosis, pyroptosis, and necroptosis. Based on this, we think there should be a new pro-inflammatory cell death PAoptosis in the form of apoptosis and pyroptosis. Circ_0004354 might compete with circ_0040039 to induce the development of IVDD by modulating miR-345-3p-FAF1/TP73 axis-mediated PAoptosis, inflammatory response, growth inhibition, and ECM degradation of NPCs. Thus, these findings offer a novel insight into the circRNAs-mediated posttranscriptional regulatory network in IVDD, contributing to further clarification of the pathological mechanism of IVDD to develop a promising therapeutic target for IVDD diseases.

Low back pain (LBP) is seriously harmful to human health and produces heavy economic burden. And most scholars hold that intervertebral disc degeneration (IDD) is the primary cause of LBP. With the study of IDD, aberrant expression of gene has become an important pathogenic factor of IDD. Circular RNAs (circRNAs), as a kind of noncoding RNA (ncRNA), participate in the regulation of genetic transcription and translation and further affect the expression of inflammatory cytokine, metabolism of extracellular matrix (ECM), the proliferation and apoptosis of cells, etc. Therefore, maybe it will become a new therapeutic target for IDD. At present, our understanding of the mechanism of circRNAs in IDD is limited. The purpose of this review is to summarize the mechanism and related signaling pathways of circRNAs in IDD reported in the past. Particularly, the roles of circRNAs in inflammation, ECM metabolism, and apoptosis are emphasized.