Psoralidin induces pyroptosis in both tumor cells and macrophages as well as enhances nature killer cell cytotoxicity to suppress hepatocellular carcinoma

Psoralidin is a major component of the traditional Chinese medicine Psoraleae Fructus, which is derived from the dried mature fruit of the leguminous plant Psoralea corylifolia L. and possesses many pharmacological effects, including anti-tumor effects. However, the mechanism through which psoralidin protects against hepatocellular carcinoma (HCC) remains unclear. In our study, we found that psoralidin induced pyroptosis and gasdermin E (GSDME) cleavage in HepG2 and Hepa1–6 cells, which were reversed by the caspase-3 inhibitor Z-DEVD-FMK. Moreover, psoralidin induced mitochondrial reactive oxygen species (ROS) production, leading to caspase-3 activation and subsequent GSDME cleavage. Interestingly, psoralidin induced pyroptosis in macrophages via ROS-NLRP3 inflammasome-gasdermin D (GSDMD), leading to the secretion of interleukin (IL)-1β and IL-18, which promoted natural killer (NK) cell activation and its anti-tumor capability. In a mouse model, psoralidin suppressed HCC growth, induced tumor cell pyroptosis, and enhanced tumor infiltration of T and NK cells. Collectively, our data demonstrate that psoralidin induces pyroptosis in tumor cells via ROS/caspase-3/GSDME and triggers pyroptosis in macrophages via ROS/NLRP3 inflammasome/GSDMD, enhancing NK cell anti-tumor ability, suggesting that psoralidin could be used as a potential therapeutic candidate for HCC.