Shenkang Injection Prevents Contrast-Induced Nephropathy byRegulating Ferroptosis Via the STAT3/HIF-1α/HMOX-1 Pathways

BACKGROUND: Contrast Medium (CM) is so toxic that it causes Contrast-Induced Nephropathy (CIN). It is the third most common cause of acute renal damage in inpatient settings. Effective therapies are scarce, and the pathophysiology of CIN is uncertain. METHODS: The active substances and potential targets of SKI、CIN, and Ferroptosis-related genes were obtained through public databases. Overlapping targets of SKI, CIN, and Ferroptosis were analyzed using Protein-Protein Interaction (PPI) networks. GO and KEGG enrichment analyses were performed to predict SKI pathways against CIN, and key components and targets were screened for molecular docking. The results of network pharmacology analysis were verified using in vitro experiments. RESULTS: Fifteen potential ferroptosis-related targets of SKI were identified for preventing CIN. GO and KEGG enrichment analyses suggest a critical role for the HIF-1 signaling pathway. In vivo experiments demonstrated that intravenous contrast agents can induce CIN under specific conditions. Biomarker (Iron, MDA, and Glutathione Peroxidase 4) analysis and mitochondrial electron microscopy provided evidence supporting the occurrence of ferroptosis. Ferrostatin-1 (Fer-1) significantly mitigates CIN by suppressing ferroptosis. SKI and Fer-1 treatment downregulated STAT3, HIF-1α, and HMOX-1 at both protein and mRNA levels, whereas CIN conditions upregulated these markers. These results were further corroborated by in vitro cell experiments. DISCUSSION: This study shows that SKI inhibits oxidative stress and ferroptosis by regulating the STAT3 / HIF-1α / HMOX-1 signaling pathway, thereby reducing the occurrence of CIN, providing valuable insights for the development of multi-target therapies for the complex pathological mechanisms of CIN. CONCLUSION: The active compound SKI significantly reduced ferroptosis in HK-2 cells induced by CM. This finding suggests that SKI is a potentially effective treatment for CIN by modulating the STAT3/HIF-1α/HMOX-1 signaling pathway.