Senkyunolide I Alleviated Renal Fibrosis in UUO Mice by Regulating the Nrf2/ xCT / GPX4 and NLRP3 /Caspase‐1/ GSDMD Pathways to Inhibit Ferroptosis and Pyroptosis

Senkyunolide I (SI), a natural phthalide compound extracted from the traditional Chinese medicine Ligusticum chuanxiong, exhibits significant potential in the treatment of fibrosis-related diseases. This study focuses on the forms of cell death as an entry point to investigate the impact of SI on renal fibrosis (RF) and related mechanisms in a unilateral ureteral obstruction (UUO) mouse model. We established a UUO mouse model for SI treatment and evaluated the alleviating effect of SI on fibrosis. We investigated how SI exerts renal protective effects by suppressing ferroptosis and pyroptosis through modulating the nuclear factor erythroid 2-related factor 2 (Nrf2)/cystine-glutamate antiporter (xCT)/glutathione peroxidase 4 (GPX4) and Nod-like receptor family pyrin domain-containing 3 (NLRP3)/cysteine-requiring aspartate protease-1 (Caspase-1)/Gasdermin D (GSDMD) axis. We found that SI effectively alleviated renal fibrosis in UUO mice by suppressing key fibrotic markers (fibronectin 1, collagen I, α-SMA) and inhibiting the TGF-β1-Smad2/3 pathway. Furthermore, through the Gene Expression Omnibus (GEO) database, we found that ferroptosis/pyroptosis has a clinical correlation with RF. Mechanistically, SI markedly reversed the abnormal changes in key markers associated with ferroptosis and pyroptosis in both in vivo and in vitro fibrosis models, and regulated the Nrf2/xCT/GPX4 and NLRP3/Caspase-1/GSDMD signaling pathways to inhibit ferroptosis and pyroptosis and exert renal protective effects. In conclusion, SI alleviated RF in UUO mice by inhibiting ferroptosis and pyroptosis, providing a directly transformable candidate molecule, new ideas, and a theoretical basis for innovative drugs targeting the intersection of ferroptosis and pyroptosis in renal fibrosis.