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New pharmacological probe tool identifies a novel negative regulatory mechanism for ferroptosis

It is one of the natural law  that small molecule compounds regulate the function of protein macromolecules. Therefore, the discovery of small molecule regulators with biological activity can not only regulate intracellular life processes, but also discover new functions of proteins. Studies on the mechanism of the natural immunosuppressive drug Rapamycin have discovered its intracellular target protein mTOR (Mammalian Target of Rapamycin), thus revealing the important role of mTOR in immune suppression and tumor therapy. mTOR is now the core molecule of research into life processes as well as a candidate molecule or mechanism for the Nobel Prize.

Previously, our research group established a new high-throughput screening (HTS) method for hydrogen sulfide gas generation enzymes (Zhou Y. et al., Chemical Communications 2013). Through screening of more than 30,000 small molecule compounds with the HTS method, 9 types of synthetic small molecules and 2 types of natural products were found to be inhibitors of hydrogen sulfide generation enzyme CBS (Zhou Y. et al., Chemical Communications 2013; Wang Li.et al., Biotechnology (Chinese Journal) 2017). In this study, the most effective CBS inhibitor CH004 (IC50 is about 1 micromolar) to date is obtained using drug design and medicinal chemistry methods through cooperation with Professor Xu Jinyi of China Pharmaceutical University. CH004  is nearly 1000 times higher than known CBS inhibitor AOAA on the cellular potency.

Further studies showed that this inhibitor could effectively inhibit the proliferation of various types of tumor cell lines, and show a potent anti-tumor growth activity in the mouse liver cancer xenograft model. Interestingly, the inhibitor can induce ferroptosis in HepG2 and MEF cells, and this induction mechanism is different from the known ferroptosis inducer Erastin. This finding reveals that the target of CH004, i.e. CBS, is a new type of negative regulatory protein for ferroptosis.

Ferroptosis is a newly discovered cell death mode, which is different from apoptosis, and previous studies have found that the cysteine/glutamate translocator System Xc- negatively regulates ferroptosis by uptake of extracellular cysteine. In this study, we first reveal that the generation of cysteine in cells can also regulate the process of ferroptosis, and CBS has a new function of negatively regulating ferroptosis. This research ccould not only provide a pharmacological probe tool for studying the gas signal pathway of hydrogen sulfide gas, but also provide a new mechanism and drug target for the treatment of diseases such as tumors.

This work was published online in field of Chemical Biology, journal of Cell Death and Disease, Nature Group (https://www.nature.com/cddis/) in September 2018. Wang li, the 2017-year master graduate of Wu Fang’s research group, is the main accomplisher  (the first author), and Cai Hao, a doctoral graduate from China Pharmaceutical University, is the co-first author. Wang li is the fourth graduate of Wu Fang's research group to publish the first or co-first research papers in internationally renowned SCI journals [ACS Chem. Bio. (Zhang Yuanyuan 2014), SCI Rep. (Lei Xiling 2015), j. Bio. Chem. (Xu Kai 2017), Cell Death and Disease (Wang Li 2018)].

                                            

Copyright: 2013 Young Scientist Laboratory of Shanghai Jiaotong University       Technical Support: Shanghai Yi-chao Information Technology Co., Ltd.