The STAT3/S100A6/P53/SLC7A11 axis mediates intervertebral disc degeneration by regulating ferroptosis in nucleus pulposus cells and the metabolism of the extracellular matrix.

BACKGROUND CONTEXT: Intervertebral disc degeneration (IVDD) may be age-related, and is often seen in evaluating patients with low back pain (LBP). However, the specific molecular mechanisms underlying IVDD remain incompletely understood.

PURPOSE: This study aims to collect nucleus pulposus (NP) tissue samples from human intervertebral discs (IVDs) at varying degeneration stages. Utilizing high-throughput proteomics and bioinformatics analysis, we seek to identify hub genes associated with IVDD, elucidate their functional mechanisms, and provide potential molecular targets and theoretical foundations for the precise treatment of IVDD.

STUDY

DESIGN

An in vivo and in vitro study.

METHODS

We performed mass spectrometry on human nucleus pulposus (NP) tissue samples and applied bioinformatics techniques to screen and identify Hub genes associated with IVDD, followed by enrichment analysis to infer their functional mechanisms. Subsequently, we employed comprehensive molecular biology and genetic approaches to validate the regulatory role of the key hub gene S100A6 in ferroptosis and extracellular matrix (ECM) metabolism. These investigations were systematically conducted across three experimental models: human NP tissue specimens, nucleus pulposus cell (NPC) cultures, and conditional S100A6 knockout mice.

RESULTS

Our data demonstrate that during IVDD, the expression of S100A6 is enhanced through transcriptional regulation by STAT3. In NPCs, the interaction between S100A6 and P53 not only promotes the expression of P53 but also enhances its phosphorylation and nuclear accumulation. Once in the nucleus, P53 suppresses the transcription of SLC7A11, thereby promoting ferroptosis in NPCs and the degradation of the ECM. Knockout of S100A6 in mice alleviates the progression of IVDD.

CONCLUSIONS

The STAT3/S100A6/P53/SLC7A11 axis plays a critical role in regulating ferroptosis and ECM metabolism in NPCs, providing promising therapeutic targets for the treatment of IVDD.

CLINICAL SIGNIFICANCE: The present investigation provides compelling evidence from human tissues, in vitro cell systems, and knockout mouse models supporting the critical involvement of the STAT3/S100A6/p53/SLC7A11 axis in IVDD progression. These discoveries suggest that pharmacological modulation of this pathway could represent a viable therapeutic approach for managing.