STAT3/POSTN/GSTP1/JNK Axis Orchestrates Ferroptosis in Nucleus Pulposus Cells: A Potential Therapeutic Target for Intervertebral Disc Degeneration.

OBJECTIVE: This study aimed to investigate the role of the STAT3/POSTN/GSTP1/JNK axis in ferroptosis and extracellular matrix (ECM) metabolic imbalance in nucleus pulposus cells (NPCs) during intervertebral disc degeneration (IDD) and to explore therapeutic strategies targeting this axis. METHODS: Using integrated multiomics sequencing, transcriptional regulation assays (chromatin immunoprecipitation, dual‑luciferase reporter), protein interaction analysis (CoIP), and other molecular biology approaches, we systematically elucidated the regulatory role of the STAT3/POSTN/GSTP1/JNK axis in ferroptosis of NPCs during IDD. Functional validation was performed in POSTN‑edited cell and rat models as well as in a needle‑puncture‑ induced rat IDD model. A small‑molecule candidate targeting this axis was identified through virtual screening, molecular docking, and molecular dynamics simulations. RESULTS: Periostin (POSTN) expression increased during ferroptosis and induced ferroptosis and ECM metabolic imbalance in NPCs in a concentration- and time-dependent manner. STAT3 was identified as a transcriptional regulator of POSTN and functionally coupled with POSTN to form a self-amplifying positive feedback loop, accelerating ferroptosis progression. Furthermore, POSTN impaired the binding of the GSTP1/JNK complex, leading to the depletion of cellular glutathione. Chemical screening identified pristimerin (PN) as a potential GSTP1-targeting compound, targeting the STAT3/POSTN/GSTP1/JNK axis and delaying IDD progression. CONCLUSION: This study identified the important role of the STAT3/POSTN/GSTP1/JNK axis in regulating ferroptosis and ECM metabolism in NPCs and highlighted PN as a promising candidate therapeutic agent for IDD. These findings provide new insights into the molecular mechanisms underlying IDD and offer new targeted therapeutic avenues for IDD.