Shikonin triggers GSDME-mediated pyroptosis in tumours by regulating autophagy via the ROS–MAPK14/p38α axis

Abstract Shikonin (SK), a botanical drug extracted from Lithospermum erythrorhizon, has been shown to inhibit tumour growth through apoptosis and necrosis. However, whether SK induces pyroptosis in cancer cells is still unknown. Here, we demonstrated that SK treatment induced gasdermin E (GSDME)-dependent pyroptosis in tumour cells. The activation of BAX/caspase-3 signalling was essential for GSDME-mediated pyroptosis by SK. Mechanistically, the intracellular reactive oxygen species (ROS) generation induced by SK treatment initiated GSDME-dependent pyroptosis. SK stimulation induced protective autophagy in a ROS-dependent manner, and repressed autophagy significantly enhanced SK-induced pyroptosis. Moreover, MAPK14/p38α, a ROS sensor, modulated SK-induced autophagy and ultimately affected GSDME-dependent pyroptosis. This study demonstrated that SK initiates ROS signalling to drive pyroptosis in cancer cells and implicates SK as having an anticancer effect by inducing tumour cell death.