Inhibition of ferroptosis ameliorates hypertensive nephropathy through p53/Nrf2/p21 pathway by Taohongsiwu decoction: Based on network pharmacology and experimental validation

Hypertensive nephropathy (HN) is a complication of hypertension. Taohongsiwu decoction (THSWD) is used clinically but its application in the prevention and treatment of HN remains unelucidated. This study aims to explore the potential targets and molecular mechanisms of THSWD in the treatment of HN. A network pharmacology approach was used to predict the components and targets of THSWD for treating HN. Animal experiments were performed to verify the network pharmacology findings. 205 targets were identified and regarded as potential targets of THSWD in HN treatment. Subsequently, we screened 17 hub genes and identified TP53 as the most critical one. KEGG enrichment analysis showed that p53 signaling pathway might play a significant role. In vivo experiments indicated that high-salt diets can lead to high blood pressure, kidney injury, inflammation, and fibrosis. Furthermore, the altered levels of biomarkers (Iron, malondialdehyde, catalase, ferritin, transferrin, Superoxide dismutase and Glutathione Peroxidase 4) provided evidence of ferroptosis. We found that the ferroptosis inhibitor ferrostatin-1 (Fer-1) and THSWD could significantly alleviate HN by suppressing ferroptosis. THSWD and Fer-1 treatment downregulated the protein and mRNA expression of p53, p21, RB, and CTNNB1, which were upregulated by high salt. Meanwhile, THSWD and Fer-1 reversed the downregulation of Nrf2 caused by high-salt diet. Our results suggested that THSWD attenuate HN induced by a high-salt diet through inhibiting ferroptosis via the p53/Nrf2/p21 pathway.