Diterpenoids from the flower buds of Daphne genkwa induced the pyroptosis of HCT-116 cells by inhibiting STAT3 phosphorylation.

Tigliane and daphnane diterpenoids are structurally and biologically diverse natural products mainly found in the Thymelaeaceae and Euphorbiaceae plant families, characterized by polyoxygenated functionalities in the polycyclic skeleton. In this study, ten undescribed polyoxygenated diterpenoids, including seven daphne yuanhuarines A-G (1-7) and three tigliane yuanhuasines L-N (8-10), along with twelve analogues (11-22), were identified from the flower buds of Daphne genkwa. The structures of them were elucidated by the methods of extensive spectroscopy and computational chemistry. 12-O-neodecanoyl-7-oxo 5-ene-phorbol-13-acetate (12) showed significant cytotoxicity against HCT-116 cells with an IC50 of 8.40 μM. Further investigation showed that 12 was able to markedly inhibit cell migration and colony formation of HCT-116 cells. HCT-116 cells, treated with 12, displayed the characteristic pyroptotic morphology of cell swelling and membrane ballooning in transmission electron microscopic assay. The mechanism investigation suggested that 12 induced the pyroptosis via caspase-3/GSDME activation by inhibiting STAT3 phosphorylation. Overall, this study showed that compound 12 was a natural pyroptosis inducer, which may facilitate the development of pyroptosis-induced anti-tumor drugs.