Developing a novel strategy for COPD therapy by targeting Nrf2 and metabolism reprogramming simultaneously

Abstract

Chronic obstructive pulmonary disease (COPD) is estimated to be the sixth major cause of disability, and the third main cause of death in the world by 2020. Although both inflammation and oxidative stress are well known to be the key predisposing factors in the pathogenesis of COPD, other elements, including metabolism, may also contribute to the exacerbation of the disease. However, the therapeutic approach which alters metabolism against COPD has yet been fully developed. Therefore, here we provide a novel therapeutic strategy for COPD patients. We first screened out the known nuclear factor erythroid-2-related factor 2 (Nrf2) activators, CPUY192018, which inhibits glycolysis, boosts antioxidative stress simultaneously and delivers satisfying therapeutic effect in macrophages from COPD patients and cigarette smoke extract induced COPD mice. Furthermore, we clarify that CPUY192018 not only disrupts the interaction between Kelch-like ECH-associated protein 1 (Keap1) and Nrf2, which liberates Nrf2 to activate the antioxidative pathway but also disrupt the interaction between Keap1 and actin which downregulates glycolysis, boosting the phagocytic function of alveolar macrophage in lung tissue. Taken together, CPUY192018 demonstrates notable effects on counteracting oxidative stress and reprogramming metabolism via Nrf2 activation; hence, being a raising potential therapeutic approach against COPD.