HIF-2α induces aggravated intervertebral disc degeneration by activating the IL-6/hepcidin-FPN1 axis and promoting ferroptosis in nucleus pulposus cells

Background Intervertebral disc degeneration (IVDD) is one of the main causes of spinal diseases and chronic low back pain. Nucleus pulposus (NP) cells are in a hypoxic environment, and their functions may be regulated by the hypoxia-inducible factor (HIF) family. In recent years, ferroptosis has been confirmed to be closely related to IVDD. HIF-2α plays a key role in hypoxic response, but its mechanism of regulating ferroptosis in IVDD remains unclear. This study aims to explore whether HIF-2α promotes ferroptosis of NP cells by activating the IL-6/hepcidin pathway and inhibiting the expression of iron transporter FPN1. Methods Primary nucleus pulposus cells from rats were cultured under normoxic and hypoxic conditions, with RSL3 and TBHP used as ferroptosis inducers. Cell viability was detected by CCK-8 assay. The expressions of HIF-2α, IL-6 and hepcidin were regulated by siRNA and overexpression plasmids. Gene and protein expressions and their interaction were analyzed by RT-qPCR, Western blot, Co-IP and immunofluorescence. A rat tail vertebra needling-induced IVDD model was established, and MRI assessment, histological staining and biochemical index detection were performed. Results Hypoxia significantly enhances the sensitivity of NP cells to ferroptosis inducers and upregulates the expression of HIF-2α. HIF-2α promotes the transcription of IL-6, thereby activating hepcidin expression, leading to the degradation of FPN1 protein, obstruction of iron efflux, intracellular iron accumulation, enhanced lipid peroxidation, and ultimately inducing ferroptosis. Animal experiments have confirmed that knocking down HIF-2α can significantly alleviate the progression of IVDD, improve tissue pathological changes, and reduce oxidative stress and ferroptosis-related indicators. Conclusion HIF-2α in IVDD promotes ferroptosis by activating the IL-6/hepcidin signaling pathway, inhibiting FPN1 expression, and thereby exacerbating intervertebral disc degeneration. Targeting this pathway may offer a new therapeutic strategy for IVDD.