Secoisolariciresinol diglucoside induces pyroptosis by activating caspase‐1 to cleave GSDMD in colorectal cancer cells

Secoisolariciresinol diglucoside (SDG) is the main component of lignans with various biological activities, including anticancer activity. However, whether SDG has obvious anticancer effects on colorectal cancer (CRC) is unclear. Pyroptosis, a form of programmed cell death, has received increasing attention in cancer‐related research. In this study, we aimed to test the anticancer properties and relatecd functional mechanisms of SDG. we found that SDG not only inhibited the cell viability of HCT116 cells, but also induced HCT116 cells to swell with apparent large bubbles, which are typical signs of pyroptosis. Furthermore, SDG induced cell pyroptosis by enhancing cleavage of the N‐terminal fragment of gasdermin D (GSDMD) in CRC cells, accompanied by increased caspase‐1 cleavage. Consistent with this, SDG‐induced GSDMD‐N‐terminal fragment cleavage and pyroptosis were reduced by siRNA‐mediated silencing of caspase‐1 or treatment with the specific caspase‐1 inhibitor VX‐765 treatment, suggesting that active caspase‐1 further induces pyroptosis. A mechanistic study showed that SDG induced reactive oxygen species (ROS) accumulation and inhibits phosphatidylinositol 3‐kinase (PI3K) phosphorylation and increases pyroptosis, while increasing GSDMD and caspase‐1 cleavage and enhancing expression of BCL2‐associated X (BAX), which could be rescued by the ROS scavenger (NAC), suggesting that SDG‐induced GSDME‐dependent pyroptosis is related to the ROS/PI3K/AKT/BAX‐mitochondrial apoptotic pathway. In vivo results showed that SDG significantly inhibited tumor growth and induced pyroptosis in the HCT116‐CRC nude mouse model. In conclusion, our findings suggest that the anticancer activity of SDG in CRC is associated with the induction of GSDMD‐dependent pyroptosis by SDG through the generation of ROS/P13K/AKT/BAK‐mitochondrail apoptosis pathway, providing insights into SDG in its potential new application in cancer treatment.