Role of Nrf2 in the pathogenesis of respiratory diseases

Nuclear factor erythroid 2-related factor (Nrf)2 is a transcription factor that integrates cellular stress signals by directing various transcriptional programs. As an evolutionarily conserved intracellular defense mechanism, Nrf2 and its endogenous inhibitor Kelch-like ECH-associated protein (Keap)1 inhibit oxidative stress in the lung, which is the internal organ that is continuously exposed to the environment. Oxidative stress is implicated in the pathogenesis of various lung diseases including asthma, acute lung injury, chronic obstructive pulmonary disease (COPD), and interstitial lung disease (ILD). Thus, Nrf2 is considered as a potential therapeutic target in lung diseases owing to its antioxidant effect. Nrf2 also plays a complex role in lung cancer, acting as a tumor suppressor and promoter; recent studies have revealed the tumor-promoting effects of Nrf2 in tumors that have undergone malignant transformation. Lung cancer-associated mutations in Keap1 disrupt Keap1–Nrf2 complex formation, resulting in the ubiquitination and degradation of Keap1, and the constitutive activation of Nrf2. In lung cancer cells, persistently high nuclear Nrf2 levels induce the expression of genes that contribute to metabolic reprogramming, and stimulate cell proliferation. In this review, we outlined the major functions of Nrf2, and discussed its importance in pulmonary diseases such as asthma, acute respiratory distress syndrome, and lung cancer. Elucidating the mechanisms through which Nrf2 modulates the initiation and progression of pulmonary diseases can lead to the development of therapeutics specifically targeting this pathway.