Hirudin inhibits ferroptosis to improve renal fibrosis by targeting the STAT3/NLRP3 signaling pathway.

Abstract

Purpose: To reveal the role and underlying mechanism of hirudin in renal fibrosis.

Methods: The unilateral ureteral obstruction (UUO) rat model and ferroptosis activator RSL3-induced human kidney proximal tubular epithelial cells (HK-2) were established. Hematoxylin-eosin staining, commercial kits, and immunohistochemistry were used to assess the effect of hirudin on renal function and renal fibrosis. Cell counting kit-8 assay was employed to test cell viability. Ferroptosis indicator levels were detected using commercial kits. The protein levels were examined by Western blot. The STAT3 activator colivelin was introduced to verify the role of the STAT3/NLRP3 signaling pathway in ferroptosis.

Results: Hirudin alleviated renal injury and improved renal fibrosis in UUO rats. The cell viability of RSL3-treated HK-2 cells was increased after hirudin treatment. In the model group, GPX4, SLC7A11, and glutathione expression decreased, while malondialdehyde and iron content levels increased, indicating that ferroptosis was activated. Besides, p-STAT3 and NLRP3 protein levels were also upregulated. However, hirudin treatment reversed these changes. When the STAT3 activator colivelin was added, the effect of hirudin was altered.

Conclusion: Hirudin improved renal fibrosis by inhibiting ferroptosis via the STAT3/NLRP3 signaling pathway.