NRF2 is a transcription factor that regulates the cellular defense against toxic and oxidative insults by activating genes involved in oxidative stress response and drug detoxification. It plays a key role in stress response, metabolism, inflammation, and other cellular processes. NRF2 activity is tightly regulated through a complex network of transcriptional and post-translational mechanisms, enabling it to respond to various stressors and maintain homeostasis. Pharmacological and genetic manipulation of NRF2 activity is associated with many metabolism- and inflammation-related diseases. Emerging evidence shows that NRF2 is at the center of a complex regulatory network and functions as a pleiotropic transcription factor. This review summarizes the complex regulatory network of NRF2 activity and its roles in metabolic reprogramming, unfolded protein response, proteostasis, autophagy, mitochondrial biogenesis, inflammation, and immunity. NRF2 regulates antioxidant stress response and drug detoxification by inducing the expression of ARE-containing cytoprotective genes. It also regulates metabolic reprogramming by affecting glycolysis, pentose phosphate pathway, fatty acid metabolism, and glutathione metabolism. NRF2 is involved in the unfolded protein response and proteostasis, and regulates autophagy, mitochondrial physiology, and inflammation. NRF2 plays a key role in maintaining mitochondrial function and biogenesis, and regulates immune responses by modulating inflammation and immunity. Overall, NRF2 is a central regulator of cellular homeostasis and has far-reaching implications in various diseases.NRF2 is a transcription factor that regulates the cellular defense against toxic and oxidative insults by activating genes involved in oxidative stress response and drug detoxification. It plays a key role in stress response, metabolism, inflammation, and other cellular processes. NRF2 activity is tightly regulated through a complex network of transcriptional and post-translational mechanisms, enabling it to respond to various stressors and maintain homeostasis. Pharmacological and genetic manipulation of NRF2 activity is associated with many metabolism- and inflammation-related diseases. Emerging evidence shows that NRF2 is at the center of a complex regulatory network and functions as a pleiotropic transcription factor. This review summarizes the complex regulatory network of NRF2 activity and its roles in metabolic reprogramming, unfolded protein response, proteostasis, autophagy, mitochondrial biogenesis, inflammation, and immunity. NRF2 regulates antioxidant stress response and drug detoxification by inducing the expression of ARE-containing cytoprotective genes. It also regulates metabolic reprogramming by affecting glycolysis, pentose phosphate pathway, fatty acid metabolism, and glutathione metabolism. NRF2 is involved in the unfolded protein response and proteostasis, and regulates autophagy, mitochondrial physiology, and inflammation. NRF2 plays a key role in maintaining mitochondrial function and biogenesis, and regulates immune responses by modulating inflammation and immunity. Overall, NRF2 is a central regulator of cellular homeostasis and has far-reaching implications in various diseases.