Objective To investigate the regulatory mechanisms of a disintegrin and metalloproteinase 17 (ADAM17) on endoplasmic reticulum stress (ERS) in cyclosporine A (CsA)-induced renal fibrosis (RF), and to identify potential novel therapeutic targets in the progression of RF. Methods A CsA-induced RF model was established in SD rats through gavage. Plasmid transfection and siRNA 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 with hematoxylin-eosin staining and Masson trichrome staining. Ultrastructural alterations were examined using transmission electron microscopy. Co-expression of ADAM17 and glucose-regulated protein 78 (GRP78) was detected by immunofluorescence. mRNA expression of TGF-β1, Smad3, α-smooth muscle actin (α-SMA), collagen typeⅠalpha 1 chain (COL1A1), ADAM17, GRP78,inositol-requiring enzyme 1(IRE1)and activating transcription factor 6 (ATF6) RT-qPCR. Protein expressions of ADAM17, Smad3, TGF-β1, α-SMA, COL1A1, and GRP78 were measured by Western blot. Results Compared with the Control-1 group, rats in the Model-1 group exhibited decreased weight(P<0. 01), increased UPCR, and significantly higher levels of serum renal function markers ( P<0. 0001 ).Morphological examinations revealed pathological changes such as renal interstitial fibrosis. The expression of RF-related indicators TGF-β1 and Smad3 was upregulated (P<0. 001), accompanied by abnormal expression of ADAM17 and GRP78 (P<0. 01). Overexpression of ADAM17 (P<0. 0001) also led to a decrease in body weight, increased UPCR,and significant increases in serum renal function markers (P<0. 01), and pathological changes associated with RF in rats. The expression levels of RF-related indicators, including TGF-β1, Smad3, α-SMA, and COL1A1, were elevated to varying degrees (P<0. 05). Meanwhile, the expression of ERS-related factors GRP78, ATF6, and PERK was upregulated to varying degrees (P<0. 05). Conversely, knockdown of the ADAM17 alleviated the aberrant expression of the aforementioned indicators to varying degrees (P<0. 05). Conclusions ADAM17 significantly promotes fibrosis progression; its dysregulation of ERS may serve as a critical mechanism underlying this pro-fibrotic process.