DEL-1 relieves bone cancer pain by targeting IL-17-triggered ferroptosis and astrocyte activation in the spinal cord.

OBJECTIVE

The core cytokine IL-17 plays a role in initiating local inflammation and stimulating the release of pro-inflammatory factors. The endogenous immune balance regulator developmental endothelial locus-1 (DEL-1) helps maintain immune homeostasis and modulates nociceptive signaling pathways. Currently, the roles and regulatory mechanisms of IL-17 and DEL-1 in bone cancer pain remain poorly understood. This study aims to investigate the effects of IL-17 and DEL-1 in alleviating bone cancer pain and to explore the specific signaling pathways involved in their regulation.

METHODS

The relevant data sets of patients with bone cancer pain and animal models were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Differentially Expressed Genes (DEGs) analysis, functional enrichment analysis and immune cell infiltration analysis were used to evaluate the activation of IL-17 signaling pathway in bone cancer pain. The regulatory effect of DEL-1 on IL-17 and its mechanism of relieving pain were further verified by behavioral tests, virus vector-mediated DEL-1 overexpression, and immunofluorescence staining in the bone cancer pain mouse model.

RESULTS

The DEGs results showed that IL-17 was significantly activated in the bone cancer pain group, accompanied by the infiltration of immune cells. In animal experiments, the expression of IL-17 was significantly up-regulated in the spinal cord of bone cancer pain mice, while the expression of DEL-1 was down-regulated. After overexpressing DEL-1, the pain behavior of bone cancer pain mice was significantly relieved, and the expression of IL-17 and the activation of astrocytes were reduced. In addition, DEL-1 overexpression could effectively inhibit the characteristics of ferroptosis in the spinal cord, including ROS accumulation, lipid peroxidation, and elevated iron ion levels.

CONCLUSION

For the first time, it was revealed that DEL-1 alleviated bone cancer pain by inhibiting IL-17-induced ferroptosis of astrocytes. This finding provides a new molecular target for the treatment of bone cancer pain, especially the intervention of DEL-1 and ferroptosis pathway may become a new therapeutic strategy.