Nrf2 signaling in chronic obstructive pulmonary disease: regulation of ferroptosis and therapeutic implications
Qian Gao, Yayun Mao, Xie Shu, Dandan Liu, Yifan Lv, Xiaodan Liu, Weibing Wu
Abstract
Chronic obstructive pulmonary disease (COPD), a major global cause of morbidity and mortality, is pathologically defined by persistent oxidative stress, chronic inflammation, and dysregulated cell death pathways. This review critically examines the emerging role of the transcription factor Nrf2 in modulating these processes within COPD, with particular emphasis on its potential regulation of ferroptosis, a novel iron-dependent form of regulated cell death implicated in disease pathogenesis. We explore the complex regulation of Nrf2, including both Keap1-dependent and -independent degradation mechanisms, as well as its upstream activators and downstream effectors in the context of COPD. Notably, we provide evidence that Nrf2 dysfunction weakens cellular defenses against oxidative stress and inflammation while increasing susceptibility to ferroptosis. Ferroptosis, marked by iron accumulation, glutathione (GSH) depletion, glutathione peroxidase 4 (GPX4) inactivation, and lipid peroxidation, is emerging as a key driver of airway epithelial damage, emphysema, and inflammation in COPD. We also delve into the molecular mechanisms of the Nrf2-ferroptosis axis, highlighting the role of Nrf2 in regulating iron homeostasis, the System Xc − /GSH/GPX4 pathway, and lipid peroxidation, with additional crosstalk to pathways like peroxisome proliferator-activated receptor gamma (PPARγ). These insights underscore the potential for targeting Nrf2-mediated ferroptosis in developing novel therapeutic approaches to combat COPD.