GATA6 Facilitates Progression of Intervertebral Disc Degeneration by Regulating Ferroptosis via Targeting TLR2/AKR1C3.

Abstract

This study explored the role of ferroptosis in intervertebral disc degeneration (IVDD), and identified GATA6 as a key regulator of this process. A ferroptosis-related gene risk coefficient model was constructed using differential gene expression analysis of the GSE70362 dataset. The analysis identified GATA6 as a significant factor in IVDD progression. GATA6 was shown to promote ferroptosis in nucleus pulposus cells (NPCs) by regulating the expression of AKR1C3 through the TLR2 pathway. In vitro and in vivo experiments demonstrated that GATA6 knockdown reduced ferroptosis, improved cell viability, and mitigated extracellular matrix degradation, whereas GATA6 overexpression exacerbated these processes. Furthermore, AKR1C3 was found to be crucial for GATA6-mediated ferroptosis, and modulation of the TLR2-AKR1C3 axis significantly impacted the degeneration of NPCs. These findings suggest that targeting GATA6 and its downstream TLR2-AKR1C3 pathway may provide new therapeutic approaches for IVDD.