Key Takeaways & Executive Findings
- •• circ_0000389 is significantly downregulated in degenerating nucleus pulposus tissues, suggesting its potential as a biomarker for IVDD. • circ_0000389 acts as a sponge for miR-346, thereby upregulating KLF7 expression and inhibiting extracellular matrix catabolism in nucleus pulposus cells. • Overexpression of miR-346 or KLF7 reverses the protective effects of circ_0000389, confirming the regulatory axis circ_0000389/miR-346/KLF7 in IVDD. • This study identifies a novel molecular mechanism and potential therapeutic target for intervertebral disc degeneration.
Abstract
Intervertebral disc degeneration (IVDD) is a major cause of low back pain. An increasing number of studies have demonstrated that circRNAs regulate the progression of IVDD. However, the specific role of circ_0000389 in the progression of IVDD is not clear. In this study, circ_0000389 is selected by bioinformatics analysis of the GSE67566 dataset. RT-qPCR is performed to detect the expressions of circ_0000389, miR-346 and KLF7 in nucleus pulposus (NP) tissues. The proliferative capacity of nucleus pulposus cells (NPCs) is examined via CCK-8 assay. Western blot analysis of extracellular matrix (ECM) catabolism is performed in NPCs. Dual-luciferase reporter gene assays and RNA immunoprecipitation (RIP) confirm the interaction of circ_0000389 with miR-346 and KLF7. The expression of circ_0000389 is significantly downregulated in degenerating NP tissues. Functionally, circ_0000389 inhibits ECM catabolism. Mechanistically, we identify miR-346 and KLF7 as downstream target genes of circ_0000389 and miR-346, respectively. miR-346 overexpression reverses the effect of circ_0000389 on NPCs, and KLF7 overexpression reverses the effect of miR-346 on NPCs, indicating that circ_0000389 alleviates IVDD progression by regulating the miR-346/KLF7 axis. This study may provide a new therapeutic target for the treatment of IVDD.
1. Introduction
Low back pain (LBP) is one of the most common health problems in the world and imposes a great burden on society [1]. Intervertebral disc degeneration (IVDD) is widely accepted as the main cause of LBP. The intervertebral disc (IVD) consists of the central nucleus pulposus, the peripheral annulus fibrosus and the cartilaginous endplates [2]. The pathogenesis of IVDD is complicated, and the main pathogenetic mechanism is considered to be related to excessive NPC death and extracellular matrix (ECM) catabolism [3]. However, there is still no effective therapeutic strategy for preventing the progression of IVDD, so further exploration of the molecular mechanisms of IVDD is urgently needed.
There is growing evidence that circRNAs are key regulators of gene expression and play important roles in regulating NPC death, ECM catabolism, and inflammatory responses by sponging microRNAs in IVDD [4,5]. Yan et al. [6] demonstrated that circ_0134111 promotes disc degeneration by sponging miR-578. Circ-GRB10 inhibits the development of IDD by alleviating the imbalance between ECM anabolism and catabolism in NPCs [7]. Du et al. [8] demonstrated that circ_0083756 promotes IVDD by targeting the miR-558/TREM1 axis. However, the role of circ_0000389 in IVDD has not yet been explored.
Accumulating studies have confirmed that multiple miRNAs play crucial roles in IVDD by modulating NPC apoptosis, aberrant proliferation, the inflammatory response, ECM catabolism and annulus fibrosus degeneration [9,10]. MiR-346, a miRNA, has been demonstrated to regulate cell proliferation [11–13], apoptosis [14] and inflammatory responses [15] in various diseases. However, the role of miR-346 in the progression of IVDD remains unclear.
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Chun Liu, Cheng Yu, Yang Duan, Jianjun Li, Xiang Chen, Wenning Xu, Sujun Qiu (2026). circ_0000389 inhibits intervertebral disc degeneration by targeting the miR-346/KLF7 axis. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025029
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Frequently Asked Questions
What is the role of circ_0000389 in intervertebral disc degeneration?
circ_0000389 is downregulated in degenerating nucleus pulposus tissues and inhibits extracellular matrix catabolism by sponging miR-346 to upregulate KLF7, thereby alleviating IVDD progression.
How does circ_0000389 regulate the miR-346/KLF7 axis?
circ_0000389 acts as a ceRNA by binding to miR-346, which prevents miR-346 from degrading KLF7 mRNA, leading to increased KLF7 expression and reduced ECM catabolism.
What methods were used to confirm the interaction between circ_0000389 and miR-346?
Dual-luciferase reporter gene assays and RNA immunoprecipitation (RIP) were used to confirm the direct interaction between circ_0000389 and miR-346, and between miR-346 and KLF7.
What is the clinical significance of this study?
The study identifies circ_0000389 as a potential therapeutic target for IVDD, offering a new strategy for treatment by modulating the circ_0000389/miR-346/KLF7 axis.
What are the key findings regarding miR-346 in IVDD?
miR-346 is a downstream target of circ_0000389 and its overexpression reverses the protective effects of circ_0000389, indicating that miR-346 promotes ECM catabolism in IVDD.
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