FIGURE 5.

Cell death pathway and the drug targets in ADPKD. In ADPKD, mutation of PKD1/PKD2 causes dysregulation of cell death, including apoptosis, autophagy and ferroptosis. Apoptosis is regulated through extrinsic pathway and intrinsic pathway. Treatment with SMAC mimetic activates apoptosis through an extrinsic dependent pathway to delay cyst growth, while treatment with pan-caspases inhibitor IDN-8050 inhibits apoptosis through an intrinsic pathway which also reduces cyst size. Treatment with SIRT-1 inhibitors, including nicotinamide and EX-527, and Smyd2 inhibitor, AZ505, as well as MIF inhibitor, ISO-1, induced apoptosis in a p53 dependent manner and delay cyst growth. Autophagy is regulated through PKD associated AMPK and mTOR pathways. Treatment with inhibitors of mTOR pathway, including NVP-BEZ236, PLD and rapamycin as well as c-Met and LAT-1 inhibitors, delays cyst growth, and treatment with AMPK inducers, metformin and HDACi, also slows cyst growth. Ferroptosis is an iron dependent cell death characterized with the increase of lipid peroxidation. Treatment with CPX-O, a chelator of iron, inhibited cystogenesis. Treatment with ferroptosis inhibitor, Ferrostatin-1, delays cyst growth and cystic cell proliferation. TMEM16A can induce lipid peroxidation, and treatment with TMEM16A inhibitor, niclosamide and benzbromarone, significantly reduced renal cyst size in ADPKD animals (Three black stars indicate drugs in clinical trials).