China News Service, Shanghai, February 1 (Reporter Xu Jing) At 0:00 on February 1, Beijing time, the important scientific discovery of Professor Wang Ping's team from Tongji University School of Medicine/Tenth Affiliated People's Hospital was published in the top international academic journal "Nature". This important discovery provides a new theoretical basis for the regulatory mechanism between metabolic homeostasis maintenance and cell fate determination, and also provides potential targets and strategies for the treatment of tumors and ischemia-reperfusion organ damage.
The paper reveals that the key enzyme of the cholesterol synthesis pathway can regulate the sensitivity of ferroptosis that is closely related to various diseases such as tumors and organ ischemia-reperfusion injury by regulating the levels of the intermediate metabolite 7-dehydrocholesterol.
Professor Wang Ping has long been committed to basic and translational research on tumor microenvironment, searching for new targets and developing new strategies for tumor intervention around the regulatory mechanisms of tumor metabolism and immune microenvironment. The expert said that by targeting the level of 7-dehydrocholesterol, it is expected to bring new ideas and new strategies to the treatment of cancer, ischemia-reperfusion organ damage and other diseases.
Programmed cell death is closely related to the occurrence and development of major diseases such as tumors and cardiovascular and cerebrovascular diseases. Ferroptosis is a new form of cell death identified in recent years that is caused by iron-dependent phospholipid peroxidation. In order to comprehensively analyze the specific regulatory mechanism of ferroptosis, the research team used genome-wide CRISPR screening technology and found that the key enzymes of the distal cholesterol synthesis pathway can differentially regulate ferroptosis sensitivity, and through a series of experiments, they identified the intermediate in the distal cholesterol synthesis pathway. Levels of the metabolite 7-dehydrocholesterol directly affect cellular sensitivity to ferroptosis.
Another important scientific discovery by Tongji University brings new ideas for the treatment of tumors, organ damage and other diseases. Photo courtesy of Tongji University
Ferroptosis plays important but distinct functions in cancer and organ ischemia-reperfusion injury diseases. The research team demonstrated that regulating the levels of 7-dehydrocholesterol by targeting the key enzymes in distal cholesterol synthesis may become a new target for clinical treatment of tumors or organ damage. In terms of tumor treatment, the research team found that the survival of some tumor cell lines depends on 7-dehydrocholesterol, and inhibiting the production of 7-dehydrocholesterol in such tumor cells can directly induce ferroptosis and inhibit tumor growth. In terms of organ damage treatment, the research team found that pharmacologically targeted inhibition of DHCR7 can effectively accumulate 7-dehydrocholesterol in the body and treat ischemia-reperfusion renal injury in mice.
Tongji University is the first unit to complete the paper, and Professor Wang Ping is the only corresponding author. Li Yaxu, a postdoctoral researcher at Tongji University School of Medicine, Ran Qiao, a doctoral candidate, Duan Qiuhui, a postdoctoral researcher, and Jin Jiali, a researcher at the Tenth Affiliated People's Hospital of Tongji University, are Co-first author of this paper. This research was funded by the National Natural Science Foundation of China’s international cooperation projects, key projects, and the National Key R&D Program of the Ministry of Science and Technology. (over)