The Repurposing of Nitazoxanide for Psoriasis Treatment Exerts Therapeutic Effects through Skin Metabolic Reprogramming.

Abstract

Nitazoxanide (NTZ), a Food and Drug Administration-approved drug, was originally developed for the treatment of parasitic infections. Recent studies have revealed that NTZ may also be effective in treating other diseases, including inflammatory diseases, cancer, and bacterial and viral infections. Therefore, we investigated whether NTZ could inhibit specific inflammatory pathways and reprogram metabolic processes in psoriasis to regulate inflammation. To investigate the symptom-alleviating effects of NTZ on psoriasis and its underlying mechanisms, we used an imiquimod-induced psoriatic-like skin inflammation mouse model and IL-17-stimulated human keratinocytes. NTZ inhibited the transition of metabolic programs induced by IL-17-mediated inflammation in human keratinocytes. In particular, NTZ suppressed glucose uptake and the associated actions stimulated by IL-17 and reduced enhanced oxidative phosphorylation. NTZ inhibited the mTOR signaling pathway by inducing AMP-activated protein kinase and prevented the development of dysfunctional mitochondria characterized by high mitochondrial mass and high levels of ROS. Moreover, the administration of NTZ in a mouse model of psoriasis, an IL-17-mediated skin disease, inhibited the accumulation of damaged mitochondria and suppressed T helper 17-mediated inflammatory responses. These findings provide preclinical evidence that NTZ may be effective in treating psoriasis and suggest that targeting the energy metabolic pathways in the skin could be beneficial for the treatment and prevention of psoriasis.