Abstract

Background Renal ischemia–reperfusion injury (RIRI), a common urological surgery complication, readily progresses to chronic kidney disease (CKD) characterized primarily by renal fibrosis. Traditional Chinese medicine Shenkangling (SKL) has significant clinical efficacy against CKD, but its active components and action mechanism remain unclear. Purpose SKL’s efficacy in improving RIRI-induced renal fibrosis, its main active components, and its potential mechanisms were investigated. Methods In a unilateral RIRI (UIRI) mouse model, pathological changes in renal tissue and fibrosis marker expression were observed after 4 weeks of SKL treatment. A TGF-β-induced HK-2 cell fibrosis model revealed improvement after treatment with SKL medicated serum (SMS). Transcriptome sequencing predicted key targets and signaling pathways, with experimental validation through methods such as western blotting, immunohistochemistry, immunofluorescence, and fluorescent probes. In the rescue experiment, inhibitors were injected in vivo, while plasmid transfection occurred in vitro. SKL’s active components were identified through pharmacochemical and molecular analyses. Results SKL significantly improved RIRI-induced renal fibrosis and reduced fibrosis marker expression. SMS improved TGF-β-induced fibrosis in HK-2 cells. STING and mitochondrial function-related signaling pathway regulation may be the primary SKL mechanism. SKL significantly suppressed STING expression, improved mitochondrial morphology, restored mitochondrial function-related protein expression, and increased mitochondrial membrane potentials. The results indicated that STING inhibition alleviated mitochondrial damage, thereby improving renal fibrosis, suggesting STING as an SKL target. SKL’s primary active components strongly bound to STING, with catalpol and loganin inhibiting TGF-β-induced fibrosis in HK-2 cells. Conclusio