A novel non-nad-based PARP1 inhibitor, Japoflavone B, triggered Caspase-3/GSDME-mediated pyroptosis through...

Pyroptosis has gotten more and more attention, in view of its link with innate immunity and disease. Most chemotherapy drugs could cause pyroptosis through caspase-3/GSDME pathway, which reshapes our understanding about the mechanism of anticancer. In our previous study, we found that a novel flavonoid, Japoflavone B (JFB), exhibited an excellent activity in vitro against the growth of cancer cells. However, the in vivo activity and molecular mechanism still need further research. Herein, JFB could particularly inhibit the proliferation of NSCLC cells, but not normal lung epithelial cells. Consistently, JFB induced inflammatory pyroptosis through the activation of Caspase-3 and GSDME, and triggered mitochondria-mediated apoptosis by activation of Caspases-3/7/9. Moreover, JFB could inhibit PARP1 activity, and promote DNA damage and ROS accumulation. Meanwhile, JFB was able to considerably promote p-p38 and p53 expression. Furthermore, the expression patterns of cyclins, CDKs, and CKIs was reprogrammed to induce cell cycle G2/M arrest with JFB treatment. In vivo, JFB exhibited a comparable anti-tumor activity to Dox with no significant tissue toxicity. Collectively, our data revealed that JFB promoted caspase-3/GSDME-mediated pyroptosis through ROS/p38/p53 pathway as a non-NAD-based PARP-1 inhibitor with high affinity and low toxicity.