Fig. 9

Schematic diagram of mechanisms underlying TPL induced pyroptosis in head and neck cancer cells. TPL simultaneously repressed c-myc/HK-II axis and NRF2/SLC7A11 axis in head and neck cancer cells. Inhibition of mitochondrial HK-II resulted in mitochondrial translocation of BAX and BAD, leading to release of cytochrome c to cytoplasm and subsequent activation of caspase 3. In GSDME ^high cancer cells, active caspase 3 cleaved GSDME at internal linker to liberate the pore-forming activity of GSDME-N, resulting in pyroptosis in cancer cells. At the same time, inhibition of NRF2/SLC7A11 by TPL led to accumulation of ROS in cancer cells, thus making cancer cells were sensitive to cytotoxicity of combination of TPL and erastin, even in GSDME^low cancer cell