The KEAP1-NRF2 regulatory system plays an important role in the oxidative stress response mechanism in living organisms; dysfunction of NRF2 has been shown to result in vulnerability to chemical and physical stress and underlies a variety of pathological conditions. NRF2 directly binds to the mediator complex subunit MED16, which is a cysteine-rich protein and whose thiol groups are modified by oxidative stress. We are trying whether MED16 functions as a nuclear redox sensor. In addition, it has become clear that stabilization of NRF2 by oxidative stress in some cells requires a previously unanticipated protein. We are challenging to elucidate its functional mechanism and physiological significance.

The PHD-HIF regulatory system is well known as an important system responsible for the cellular response to hypoxia. However, we have found that when hypoxia persists, a completely different system, the PNPO-PLP regulatory system, is activated. PHD-HIF regulatory system alters transcription via rapid response to acute hypoxia by stabilizing HIF proteins, resulting in metabolic changes, including enhancement of the glycolytic system. In contrast, the PNPO-PLP regulatory system decreases PLP in persistent chronic hypoxia by decreasing PNPO activity, which in turn leads to transcriptional changes by suppressing PLP-dependent metabolism. We hope to clarify the importance of the PNPO-PLP regulatory system in cells and tissues under physiological hypoxia.

Sulfur is an element that has been a driving force in the history of life on Earth since life began in the ancient seas. Compared to oxygen, the change in energy associated with the transfer of electrons is small, so it is thought that sulfur was an element that organisms could easily use as a tool for redox reactions. Sulfur is also the only element that forms a catenation (linear linkage) on its own, and is known to exist in a wide variety of allotropes. Metabolites and proteins with sulfur catenation are collectively referred to as supersulfides. The presence of supersulfides in living organisms has been overlooked because of their high reactivity and the difficulty of measuring them. However, with the recent development of new qualitative and quantitative techniques for sulfur metabolites, it has become clear that a wide variety of supersulfides exist in abundance in living organisms. Low-molecular-weight supersulfides have been shown to be universal and essential life elements, responsible for energy production, antioxidant and anti-inflammatory effects. It is also becoming clear that the cysteine side chains of proteins are frequently supersulfidated, which is involved in protein quality control and signal transduction. We are using genetically engineered mice to try to elucidate the role of supersulfides in mitochondria and cytoplasm.

In normal cells, NRF2 is ubiquitinated by binding to KEAP1 and degraded by proteasomes. However, in lung, head and neck, and esophageal cancers, mutations in the KEAP1 and NRF2 (NFE2L2) genes impair NRF2 degradation, resulting in a persistently activated state of NRF2. Other causes of NRF2 stabilization have also been reported. Constantly activated NRF2 enhances the stress response capacity of cancer cells. As a result, NRF2-activated cancers are less likely to respond to treatment with anticancer agents or radiation, which is one of the causes of poor prognosis. In recent years, it has become clear that NRF2-activated cancers are resistant to immunotherapy, and we are currently investigating the cause of this resistance in order to obtain new therapeutic strategies.

Inflammatory bowel disease (IBD) is a chronic intractable disease with a relatively young age of onset and a long-term course with repeated remissions and relapses, and the number of patients has been increasing in recent years. It is becoming increasingly clear that the etiology of the disease is a dysregulation of immune response and inflammation, mainly in the intestinal tract. On the other hand, we have inadvertently discovered that modification of aminic acid metabolism in the intestinal epithelium may alleviate the pathophysiology of inflammatory bowel disease by improving its barrier function. We are conducting our research with the expectation that this will lead to the development of therapeutic agents that target the intestinal epithelium instead of the immune system.