Astragaloside IV attenuates oxidative stress-associated mitophagy-dependent ferroptosis in peritoneal mesothelial cells via suppression of STAT3 signaling.

BACKGROUND: Peritoneal injury and subsequent fibrosis driven by oxidative stress are major contributors to peritoneal dialysis (PD) withdrawal. Ferroptosis and mitophagy are closely correlated with oxidative stress, but their roles and interplay in PD-related peritoneal injury remain incompletely defined. Astragaloside IV (AS-IV) has shown anti-fibrotic and antioxidant potential, yet its underlying mechanism in this context is not fully understood. This study aims to investigate the involvement of mitophagy and ferroptosis during PD and to evaluate whether AS-IV attenuates PD-related peritoneal injury by targeting mitophagy-dependent ferroptosis via STAT3 signaling. METHODS: Mouse models of peritoneal fibrosis were established using either methylglyoxal or PD fluid (PDF). Peritoneal tissues were analyzed by histopathology and Western blotting, and serum malondialdehyde was measured. In vitro, human peritoneal mesothelial cells (PMCs; HMrSV5) were assigned to different groups and exposed separately to PDF, carbonyl cyanide m-chlorophenylhydrazone, erastin, or colivlin, followed by separate treatment with N-acetylcysteine, mitochondrial division inhibitor 1, S3I-201, or AS-IV. Ferroptosis and mitophagy were assessed by fluorescence staining and Western blotting, and mitochondrial ultrastructure was evaluated by transmission electron microscopy. RESULTS: PDF exposure induced oxidative stress-associated mitophagy and ferroptosis in PMCs, with evidence supporting a close association between these processes. AS-IV treatment attenuated STAT3 activation, reduced mitophagy-related changes, and alleviated ferroptosis and peritoneal injury. CONCLUSION: Oxidative stress-associated, mitophagy-dependent ferroptosis contributes to PD-related peritoneal injury. AS-IV attenuates this process via suppression of STAT3 signaling in PMCs.