1. Introduction

Under normal conditions, NRF2 is negatively regulated by three E3 ubiquitin ligase complexes: the KEAP1-cullin 3 (CUL3)-ring box 1 (RBX1) complex, the β-TrCP-S-phase kinase-associated protein 1 (SKP1)-CUL1-RBX1 complex, and the Hmg-CoA reductase degradation protein 1 (HRD1) [29,98,99,100]. However, when the organism is exposed to endogenous and environmental stresses, NRF2 degradation is interrupted by the inhibition of the UPS, and newly translated NRF2 translocates to the nucleus, binds to sMAF proteins, and transcribes ARE-driven genes. The extensive cytoprotective genes regulated by NRF2 are crucial for suppressing the oxidative, proteotoxic, and metabolic stresses which facilitate malignant transformation. The transient activation of NRF2 during stress is beneficial to health, while a sustained activation of NRF2 has detrimental effects.

A large body of evidence shows that KEAP1 has become a crucial regulator of the NRF2-mediated signaling pathway. It is generally believed that KEAP1 can function as a molecular switch to sense the imbalance in redox homeostasis and turn on or off the NRF2 signaling pathway [101,102]. Under general conditions, the activity of NRF2 is negatively regulated by KEAP1. During stress, NRF2 upregulation can be induced by oxidative or electrophilic modification of KEAP1 cysteines (i.e., Cys151), which suppresses the formation of the NRF2–KEAP1 complex and results in diminished NRF2 ubiquitination, thereby initiating the canonical NRF2 signaling pathway [103,104,105,106]. Thus, newly translated NRF2 translocates to the nucleus, binds to sMAF proteins, and transcribes ARE-regulated cytoprotective target genes to maintain redox homeostasis [20]. When redox homeostasis is restored, KEAP1 travels into the nucleus to dissociate NRF2 from the ARE and returns NRF2 to the cytosol for ubiquitination and degradation to inhibit the sustained activation of NRF2 [107]. This pattern of NRF2-activation regulation is an immediate consequence of oxidative or electrophilic stresses and is referred to as “canonical activation”. In terms of chemoprevention, NRF2 has been shown to be activated via the canonical mode by various dietary compounds or synthetic chemicals [108]. The treatment strategies for many diseases, including cancer, are based on utilizing the protective capacity of the NRF2 response, which is achieved by transient NRF2 activation via oxidative or electrophilic modification of KEAP1 [109,110,111,112]. Therefore, the canonical activation of NRF2 is crucial to switch on the detoxification of harmful carcinogens and relieve excessive stress to avoid malignant transformation.

Another important pathway during stress is the autophagy-lysosome pathway, a highly regulated cellular degradation pathway which is responsible for removing damaged, degenerative, and aging proteins and organelles, such as oxidatively damaged proteins and dysfunctional mitochondria. Autophagy dysfunction leads to the accumulation of pathogenic proteins and organelles, which is the root cause of many diseases, including metabolic disorders, neurodegenerative diseases, infectious diseases, cardiovascular diseases, and cancer [113,114]. To some extent, autophagy pathway dysfunction is associated with NRF2 activation. For instance, several studies have found that NRF2 can be activated through autophagy inhibition in a p62-dependent but Keap1-Cys151-independent manner, which is known as “non-canonical activation” [115,116,117,118]. Autophagy dysfunction has been shown to induce the accumulation of p62, a selective autophagy adaptor, which leads to the sequestration and loss of function of numerous binding partners, including KEAP1 [115,119,120]. p62 interacts directly with KEAP1 through its KEAP1-interacting region (KIR), which contains a DPSTGE motif similar to the ETGE motif in NRF2 for KEAP1 binding [117,121]. The KEAP1 sequestration by p62 stabilizes NRF2, which can initiate the transcription of target genes, including p62, creating a positive feedback loop and prolonging NRF2 activation [119]. However, the excessive accumulation of p62 induces sustained NRF2 activation, which facilitates the formation and development of tumors [122]. Deletion of p62 consistently inhibits NRF2 activation and arsenic-induced malignant transformation of human keratinocytes [123]. The relationship between the non-canonical activation of NRF2 and carcinogenesis must be thoroughly investigated to identify a potential target for cancer treatment or prevention.

NRF2 has traditionally been considered a tumor suppressor since the NRF2–KEAP1 signaling pathway is an essential cell protection mechanism that can defend against oxidative/electrophilic stresses and promote cell survival. The activation of the NRF2 pathway induced by natural compounds is an effective chemoprevention strategy [124]. Moreover, NRF2-deficient mice are more susceptible to develop cancer, and NRF2 deficiency is associated with cancer metastasis [125,126,127,128].

Transient activation of NRF2 during stress is beneficial to normal cells, whereas hyperactivation of NRF2 facilitates the survival of normal as well as malignant cells. Recent evidence suggests that the “dark” side of NRF2 may be mediated by excessive accumulation of p21 and p62 via disruption of NRF2–KEAP1 interactions [115,129]. In addition, NRF2 can exert a significant action of chemoresistance, inhibiting drug accumulation in cancer cells, and thereby contributing to survival of cancer cells. Considering the pro-tumorigenic effect of NRF2 in cancer cells, pharmacological suppression of the NRF2 pathway will emerge as a promising area of cancer research. Several groups have identified many NRF2 pharmacological inhibitors, such as brusatol, halofuginone, luteolin, and procyanidin [130,131,132,133]. However, there is currently no FDA-approved drug to suppress NRF2 activation. Therefore, extensive research is required to identify drugs that can prevent and treat cancer.

4. Crosstalk between the STAT3 and NRF2 Signaling Pathways in the Tumor Microenvironment