Multi-omics Unveils the Integrative of Qingzhuo Huayu Formula in Alleviating Chronic Kidney Disease Progression: Gut Microbiota Remodeling, Metabolic Reprogramming, and Ferroptosis Suppression

Background and Purpose Chronic kidney disease (CKD) is a global health concern with limited therapeutic options. The traditional Chinese medicine formulation, Qingzhuo Huayu Formula (QZHYF), has demonstrated clinical promise, yet its underlying mechanisms remain poorly understood. Experimental Approach A 7-month clinical trial in CKD patients was combined with an Adriamycin-induced nephropathy rat model. Multi-omics, histopathological, and molecular biology analyses assessed the effects of QZHYF on renal function, microbial composition, and key molecular pathways associated with inflammation and cell death. Key Results Clinically, QZHYF improved renal function, corrected electrolyte imbalances, and attenuated NF-κB-driven microinflammation. It remodeled the gut microbiota by enriching Lactobacillus and suppressing Escherichia-Shigella , enhancing intestinal barrier integrity, and reducing gut-derived toxins. Serum metabolomics showed that QZHYF downregulated nephrotoxic metabolites such as kynurenic acid, increased glycine levels, which is crucial for glutathione synthesis, and normalized tryptophan metabolism, thereby creating a metabolic environment that mitigates ferroptosis. QZHYF intervention alleviated renal damage in CKD rats by attenuating tubular epithelial cell edema and cytoplasmic condensation, suggesting inhibition of ferroptosis. At the molecular level, QZHYF alleviated oxidative stress and cell death by synergistically inhibiting the p38 MAPK and PI3K/AKT signaling pathways. This dual inhibition not only reduced inflammation but also shaped an intracellular environment unfavorable to ferroptosis. Conclusion and Implications This study reveals that QZHYF slows CKD progression by modulating the gut microbiota, reprogramming host metabolism, and inhibiting key pathways involved in ferroptosis. These findings provide a mechanistic basis for the potential clinical use of QZHYF and offer new therapeutic insights for CKD.