INTRODUCTION: Chronic nephrotoxicity caused by CNIs (CICN) manifests clinically as chronic kidney disease (CKD). Astragaloside IV (AS-IV) plays a certain role in the treatment of CKD. This study aimed to verify the ameliorative effects of AS-IV on CICN and further explore the mechanisms underlying the modulation of the "gut-transcriptome-metabolome coexpression network" by AS-IV within the context of the "gut-kidney axis" to improve CICN. METHODS: Five groups of 40 mice were studied: a normal group (N, olive oil), a model group (M, CsA, 30 mg kg RESULTS: CsA led to increased proteinuria and a deterioration of kidney function, accompanied by increased inflammation and oxidative stress, whereas AS-IV improved kidney damage. AS-IV inhibited intestinal permeability and disrupted the microbiota structure, increasing the abundance of CONCLUSION: AS-IV improved CICN through the coexpression of the gut-transcriptome-metabolome network. The six pathways related to energy metabolism driven by