Astragaloside IV Alleviates Peritoneal Dialysis-Related Peritoneal Fibrosis by Regulating HIF-1α-Mediated Autophagy

Background Peritoneal fibrosis (PF) is a major complication of long-term peritoneal dialysis (PD). Dysregulated hypoxia-inducible factor-1α (HIF-1α) disrupts autophagic homeostasis, accelerates epithelial-mesenchymal transition (EMT) and aggravates PF. This study investigated the therapeutic effect of Astragaloside IV (AS-IV) against PF and its mechanism targeting HIF-1α-dependent autophagy. Methods: Network pharmacology and molecular docking predicted core targets of AS-IV, followed by in vitro and in vivo validation. TGF-β1-stimulated HMrSV5 cells and HIF-1α overexpression cell model were applied, with interventions of AS-IV, dimethyloxalylglycine (DMOG), and 3-methyladenine (3-MA). Western blot, immunofluorescence, RT-qPCR and transmission electron microscopy were performed to detect signaling, autophagy and EMT markers. A rat PF model induced by peritoneal dialysate combined with lipopolysaccharide (LPS) was established; histological and molecular assessments were conducted on peritoneal tissues after AS-IV or losartan treatment. Results: HIF1A and MTOR were identified as core targets. Molecular docking confirmed stable binding between AS-IV and HIF-1α/mTOR proteins. In vitro, AS-IV suppressed HIF-1α/mTOR hyperactivation, restored autophagy and inhibited TGF-β1-triggered EMT. DMOG or 3-MA abolished the protective functions of AS-IV. In vivo, AS-IV mitigated peritoneal pathological injury, inhibited HIF-1α/mTOR signaling, restored autophagic activity and blocked EMT progression, showing efficacy comparable to losartan. Conclusion AS-IV alleviates PD-related PF by regulating HIF-1α-mediated autophagy. These are preclinical findings, further genetic validation and autophagic-flux detection are required to confirm causal relationships.