Deoxynivalenol (DON), a frequent food and feed contaminant, poses a severe threat to human and livestock health. Some studies have demonstrated that DON could induce liver damage and cell death. However, novel cell death styles and detailed mechanisms to explain DON-induced liver inflammatory injury are still lacking. Here, we found both chronic and subacute
oral administration of DON (3 mg/kg for 4 weeks and 4 mg/kg for 8 days) induced mouse liver inflammatory injury and activated
caspase-3, PARP and gasdermin E (GSDME), which were inhibited by
caspase-3 inhibitor Z-DEVD and Ac-DEVD. In vitro, HepaRG cells showed typical pyroptotic characteristics after 32 and 64 μM DON exposure for 24 h, including balloon-like bubbling emerging, release of
lactate dehydrogenase (LDH), secretion of IL-1β and
IL-6 and activation of
caspase-3 and GSDME. Furthermore, knocking down GSDME and inhibiting
caspases activity by Z-VAD and Z-DEVD dramatically blocked DON-induced pyroptotic characteristics, while over-expressed GSDME prompted that. These data demonstrate that
caspase-3/GSDME pathway plays a key factor in DON-induced pyroptosis and
inflammation in liver. Interestingly, knocking down GSDME could inhibit DON-induced pyroptosis but prompt DON-induced apoptosis, while opposite results were obtained when over-expressed GSDME, indicating the critical role of GSDME in DON-induced crosstalk between apoptosis and pyroptosis. Taken together, our data determine DON-induced
caspase-3/GSDME-dependent pyroptosis in liver and its role in DON-induced liver inflammatory injury, which provide a novel mechanistic view into DON-induced hepatotoxicity and may offer a new target to reduce latent harm of DON to both humans and animals.