Combined treatment with metformin and cinacalcet significantly reduces cyst growth of human 3D cells derived from ADPKD cyst-lining epithelia and restores the altered bioenergetic profile

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is caused by mutations in PKD1 or PKD2 genes and is characterized by abnormal cell proliferation and fluid secretion, leading to the formation and progressive enlargement of kidney cysts. Therapeutic treatments with either cinacalcet or metformin have emerged as a potential therapeutic approach to slow renal cystogenesis in ADPKD. Metformin, a drug in wide clinical use, is a pharmacological activator of AMPK, whose activity is abnormally suppressed in the context of ADPKD. On the other hand, cinacalcet, a calcium sensing receptor drug activator, has been shown to reduce cyst enlargement and cell proliferation in ADPKD cells. Here we provide evidence that combined treatment with metformin (200 µM for 3 days) and cinacalcet (1nM for 3 days) significantly reduced forskolin-induced cyst growth of human 3D cells derived from ADPKD cyst-lining epithelia. With respect to the single administration, the combined treatment had a synergistic effect in reducing S6 ribosomal protein phosphorylation (marker of mTORC1), that is early increased in ADPKD. Moreover, the dual treatment fully restored the altered bioenergetic profile observed in ADPKD cells, including improvements in mitochondrial ATP production and the multilevel impairment of oxidative phosphorylation. Together these data suggest that the combination of the two drugs has an additive beneficial effect, making the proposed study promising for therapeutic investigation. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.