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ADPKD is characterized by progressive cyst formation and enlargement leading to kidney failure. Tolvaptan is currently the only FDA-approved treatment for ADPKD; however, it can cause serious adverse effects including hepatotoxicity. There remains an unmet clinical need for effective and safe treatments for ADPKD. The extracellular Ca 2+ -sensing receptor (CaSR) is a regulator of epithelial ion transport. FDA-approved CaSR activator cinacalcet can reduce cAMP-induced Cl - and fluid secretion in various epithelial cells by activating phosphodiesterases (PDE) that hydrolyze cAMP. Since elevated cAMP is a key mechanism of ADPKD progression by promoting cell proliferation, cyst formation and enlargement (via Cl - and fluid secretion), here we tested efficacy of cinacalcet in cell and animal models of ADPKD. Cinacalcet treatment reduced cAMP-induced Cl - secretion and CFTR activity in MDCK cells as suggested by ∼70 % lower short-circuit current (I sc ) changes in response to forskolin and CFTR inh -172, respectively. Cinacalcet treatment inhibited forskolin-induced cAMP elevation by 60 % in MDCK cells, and its effect was completely reversed by IBMX (PDE inhibitor). In MDCK cells treated with forskolin, cinacalcet treatment concentration-dependently reduced cell proliferation, cyst formation and cyst enlargement by up to 50 % without affecting cell viability. Cinacalcet treatment (20 mg/kg/day for 7 days, subcutaneous) reduced renal cyst index in a mouse model of ADPKD (Pkd1 flox/flox ;Ksp-Cre) by 20 %. Lastly, cinacalcet treatment reduced cyst enlargement and cell proliferation in human ADPKD cells by 60 %. Considering its efficacy as shown here, and favorable safety profile including extensive post-approval data, cinacalcet can be repurposed as a novel ADPKD treatment., Competing Interests: Declaration of Competing Interest All authors have read the journal's policy on disclosure of potential conflicts of interest and have none to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)