Objective To investigate the regulatory mechanisms of a disintegrin and metalloproteinase 17 (ADAM17)?and endoplasmic reticulum stress (ERS) in cyclosporine A (CsA)-induced renal fibrosis, and to identify potential novel therapeutic targets in the progression of renal fibrosis.Methods A CsA-induced renal fibrosis model was established in SD rats via gavage. Plasmid transfection and siRNA technologies were employed to overexpress or knock down ADAM17 in vivo. Indices including body weight,urine protein/creatinine ratio (UPCR),serum blood urea nitrogen (BUN), serum creatinine (Scr), cystatin C (Cys-C),transforming growth factor-β1 (TGF-β1), and ADAM17 were measured. Pathological changes in kidney tissues were observed via hematoxylin-eosin (HE) staining and Masson's trichrome staining. Ultrastructural alterations were examined using transmission electron microscopy (TEM). Co-expression of ADAM17 and glucose-regulated protein 78 (GRP78) was detected by immunofluorescence. mRNA expressions of TGF-β1， SMAD homolog 3 (SMAD3),α-smooth muscle actin (α-SMA), collagen type I alpha 1 chain (COL1A1),ADAM17,and GRP78 in kidney tissues were analyzed via reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR). Protein expressions of ADAM17,SMAD3, TGF-β1, α-SMA,COL1A1, and GRP78 were measured by Western blotting (WB).Results In the CsA-induced model group, rats exhibited decreased body weight,significantly increased UPCR,serum renal function indicators (BUN, Scr,Cys-C), serum ADAM17, and serum TGF-β1 levels (p < 0.01). Morphological examinations revealed pathological changes such as renal interstitial fibrosis. RT-qPCR showed upregulated mRNA expressions of TGF-β1,SMAD3,and ADAM17 (p < 0.01), while WB demonstrated significantly elevated protein levels of TGF-β1, SMAD3,and ADAM17 (p < 0.01). Overexpression of ADAM17 (p < 0.001) led to a marked decrease in body weight,significant increases in serum renal function indicators and UPCR (p < 0.01), and typical pathological changes including renal interstitial fibrosis. Immunofluorescence, RT-qPCR,and WB all showed increased GRP78 expression,along with abnormal upregulation of TGF-β1,SMAD3, COL1A1, α-SMA, and other indicators (p < 0.01). Conversely, knockdown of the ADAM17 gene in the model group alleviated these abnormal expressions to varying degrees (p < 0.05).Conclusions ADAM17 significantly promotes fibrosis progression, and its dysregulation of endoplasmic reticulum stress (ER stress) may serve as a critical mechanism underlying this pro-fibrotic process.