Targeting microtubule dynamics with mebendazole slows disease progression in ADPKD mice

Abstract Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder and is primarily caused by mutations in PKD1 or PKD2. The disease is characterized by the progressive development and enlargement of fluid-filled renal cysts over decades. Microtubules (MTs) are highly dynamic cytoskeletal structures that continuously alternate between growth and shortening to support a wide range of cellular processes, including cell proliferation. Here, we investigated whether dysregulated MT dynamics contribute to cyst formation. We demonstrate that MT dynamics are enhanced in Pkd1 -deficient cells through activation of GSK3β, which promotes MT growth by phosphorylating end-binding protein 1 (EB1) at serine 155. Furthermore, treatment with mebendazole, an anthelmintic that disrupts MT polymerization, slowed cyst progression and improved renal function in a Pkd1 ADPKD mouse model. These findings identify enhanced MT dynamics as a previously unrecognized mechanism contributing to ADPKD pathogenesis and suggest that mebendazole may represent a potential therapeutic strategy for this disease.