It is well-known that microbiota dysbiosis is closely associated with numerous diseases in the human body. The oral cavity and gut are the two largest microbial habitats, playing a major role in microbiome-associated diseases. Even though the oral cavity and gut are continuous regions connected through the gastrointestinal tract, the oral and gut microbiome profiles are well-segregated due to the oral–gut barrier. However, the oral microbiota can translocate to the intestinal mucosa in conditions of the oral–gut barrier dysfunction. Inversely, the gut-to-oral microbial transmission occurs as well in inter- and intrapersonal manners. Recently, it has been reported that oral and gut microbiomes interdependently regulate physiological functions and pathological processes. Oral-to-gut and gut-to-oral microbial transmissions can shape and/or reshape the microbial ecosystem in both habitats, eventually modulating pathogenesis of disease. However, the oral–gut microbial interaction in pathogenesis has been underappreciated to date. Here, we will highlight the oral–gut microbiome crosstalk and its implications in the pathogenesis of the gastrointestinal disease and cancer. Better understanding the role of the oral–gut microbiome axis in pathogenesis will be advantageous for precise diagnosis/prognosis and effective treatment.

The nuclear factor-erythroid 2 p45-related factor 2 (NRF2, also called Nfe2l2) and its cytoplasmic repressor, Kelch-like ECH-associated protein 1 (KEAP1), are major regulators of redox homeostasis controlling a multiple of genes for detoxification and cytoprotective enzymes. The NRF2/KEAP1 pathway is a fundamental signaling cascade responsible for the resistance of metabolic, oxidative stress, inflammation, and anticancer effects. Interestingly, a recent accumulation of evidence has indicated that NRF2 exhibits an aberrant activation in cancer. Evidence has shown that the NRF2/KEAP1 signaling pathway is associated with the proliferation of cancer cells and tumerigenesis through metabolic reprogramming. In this review, we provide an overview of the regulatory molecular mechanism of the NRF2/KEAP1 pathway against metabolic reprogramming in cancer, suggesting that the regulation of NRF2/KEAP1 axis might approach as a novel therapeutic strategy for cancers.

Signal transducer and activator of transcription 3 (STAT3) functions as a major molecular switch that plays an important role in the communication between cytokines and kinases. In this role, it regulates the transcription of genes involved in various biochemical processes, such as proliferation, migration, and metabolism of cancer cells. STAT3 undergoes diverse post-translational modifications, such as the oxidation of cysteine by oxidative stress, the acetylation of lysine, or the phosphorylation of serine/threonine. In particular, the redox modulation of critical cysteine residues present in the DNA-binding domain of STAT3 inhibits its DNA-binding activity, resulting in the inactivation of STAT3-mediated gene expression. Accumulating evidence supports that STAT3 is a key protein that acts as a mediator of metabolism and mitochondrial activity. In this review, we focus on the post-translational modifications of STAT3 by oxidative stress and how the modification of STAT3 regulates cell metabolism, particularly in the metabolic pathways in cancer cells.

Redox homeostasis is not only essential for the maintenance of normal physiological functions, but also plays an important role in the growth, survival, and therapy resistance of cancer cells. Altered redox balance and consequent disruption of redox signaling are implicated in the proliferation and progression of cancer cells and their resistance to chemo- and radiotherapy. The nuclear factor erythroid 2 p45-related factor (Nrf2) is the principal stress-responsive transcription factor that plays a pivotal role in maintaining cellular redox homeostasis. Aberrant Nrf2 overactivation has been observed in many cancerous and transformed cells. Uncontrolled amplification of Nrf2-mediated antioxidant signaling results in reductive stress. Some metabolic pathways altered due to reductive stress have been identified as major contributors to tumorigenesis. This review highlights the multifaceted role of reductive stress in cancer development and progression.