Repositioningofniclosamideethanolamine(NEN), ananthelminticdrug, for thetreatmentoflipotoxicity

Abstract

Nonalcoholic steatohepatitis (NASH) is a common liver disease associated with metabolic disorders, including obesity and type 2 diabetes (T2D). Despite its worldwide prevalence, there are no effective drugs for thetreatmentof NASH. The progression of NASH is mainly accelerated by reactive oxygen species (ROS)-inducedlipotoxicity. The transcription factor known as nuclear factor erythroid 2-related factor 2 (Nrf2) is pivotal for the elimination of ROS. Accordingly, activators of Nrf2 have been implicated as promising therapeutic targets for thetreatmentof NASH.Niclosamide(ethanolaminesalt;NEN), adrugapproved by the US Food andDrugAdministration (USFDA), is currently used as ananthelminticdrugfor thetreatmentof parasitic infections. Recently,NENwas shown to improve hepatic steatosis in high-fat diet (HFD)-fed mice. However, the underlying mechanism of its antioxidant function in NASH remains unknown. Here, we demonstrate thatNENinduces AMPK-mediated phosphorylation of p62 at S351 that can lead to noncanonical Nrf2 activation. We also demonstrate thatNENprotects cells and mouse liver from acute lipotoxic stress through activating p62-dependent Keap1-Nrf2 pathway. Taken together,NENcan be used for clinical applications and has the potential to provide a new therapeutic option for NASH.