Xanthoangelol modulates Caspase-1-dependent pyroptotic death among hepatocellular carcinoma cells with high expression of GSDMD

Abstract

• XAG exhibits anti-proliferation in HuH7 and HepG2 cells. • XAG induces pyroptotic death in HuH7 cell line with concomitant activation of NLRP3/Caspase-1/GSDMD pathway. • XAG modulates caspase-1-dependent apoptosis in GSDMD-low HepG2 cells. • XAG functions as an anti-tumor agent by restraining the activation of MAPK and NF-κB signaling pathways. Xanthoangelol (XAG), a major chalcone presents in Angelica keiskei , has been employed in research to develop functional supplements or drugs due to its various pharmacological activities. Here, we investigated the underlying mechanism of XAG-induced cell death in hepatocellular carcinoma (HCC). We found that XAG inhibited the cell viability of either HepG2 or HuH7cells, and induced pyroptotic death in HuH7 cell with concomitant activation of NOD-like receptor family pyrin domain containing 3 (NLRP3)/Caspase-1/gasdermin D (GSDMD) pathway. However, in GSDMD-low HepG2 cells, Caspase-1 expression modulated the underlying XAG-induced apoptosis pathway, thereby regulating cell death. VX-765, a special inhibitor of caspase-1, attenuated XAG-induced pyroptosis and apoptosis. Additionally, mitogen-activated protein kinase (MAPK) and NF-κB signaling pathway were suppressed by XAG. These findings suggest that XAG is a promising therapeutic agent through induction of caspase-1 mediated pyroptosis and apoptosis depend on the expression of GSDMD in HCC cells.