NAMPT Overexpression Drives Cell Growth in Polycystic Liver Disease Through Mitochondrial Metabolism Regulation.

A group of genetic diseases known as polycystic liver disease (PLD) are distinguished by the gradual development of fluid-filled hepatic cysts formed from cholangiocytes and commonly related to primary cilia defects. The NAD salvage pathway, which sustains cellular bioenergetics and supplies a required substrate for tasks important to rapidly multiplying cells, has a rate-limiting phase that is mediated by NAMPT. In this study, the efficacy and mechanisms of action of FK866, a novel, high-potency NAMPT inhibitor with a good toxicity profile, were assessed. NAMPT-siRNA and FK866 reduced NAD levels and inhibited the proliferation of PLD cells in a dose-dependent manner. Notably, this pharmacological and si-RNA-mediated suppression of NAMPT was less effective in normal cells at the same concentrations. The addition of NMN, a byproduct of NAMPT that restored NAD concentration, rescued the cellular viability of PLD cells and verified the on-target action of FK866. In PLD cells, FK866 treatment impairs mitochondrial respiration and ATP production and induces ROS production. Importantly, FK866 treatment showed improved effects of octreotide, a drug used for PLD treatment. As a result, the use of NAMPT inhibitors, including FK866 therapy, offers the possibility of a further targeted strategy for the therapeutic treatment of PLD.

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