Echinococcus granulosus-Induced Liver Damage Through Ferroptosis in Rat Model.

(1) Background: Cystic echinococcosis (CE) is an Echinococcus granulosus-induced worldwide parasitic zoonosis and is a recognized public health and socio-economic concern. The liver is the major target organ for CE's infective form protoscolex (PSCs), which causes serious liver damage and endangers the host's life. Reports show that PSC infection causes liver cell Fe(2+) metabolism disorder and abnormal deposition of Fe(2+) in liver cells and results in liver cell death. However, whether PSC-induced liver cell death is associated with ferroptosis remains to be clarified. (2) Methods: Using both an in vivo rat model and an in vitro co-culture of PSCs and the cell system, we studied the histopathological progress of PSCs infection and the cytopathogenesis of PSC-induced cell death in the liver. Hepatic-injury-related ferroptosis signaling pathways were identified by proteomics analysis at various stages of PSCs infection, and physiological and the biochemical indexes and expression of pathway proteins related to hepatic ferroptosis were studied. Ferrostatin-1, a ferroptosis inhibitor, was employed for in vivo interference with early protoscolices infection in rats, and the effects of the inhibition of hepatocyte ferroptosis on hepatocyte injury and the generation of fibrotic cysts were investigated. Additionally, PSCs were exposed to in vitro co-culture with BRL, a rat hepatocyte line, to clarify the direct influences of PSCs on BRL ferroptosis. (3) Results: The results of our in vivo studies revealed that PSCs infection induced Fe(2+) enrichment in liver cells surrounding the PSCs cysts, cellular oxidation, and liver tissue damage along with the prolongation of PSCs parasitism. The results of our in vitro studies verified the ability of PSCs to directly induce ferroptosis, the formation of fibrotic cysts, and alteration of the iron metabolism of liver cells. The analysis of KEGG signaling pathways revealed that ferroptosis- and ROS-related pathways were significantly induced with PSCs infection. Using Ferrostatin-1 effectively blocked ferroptosis, reversed Fe(2+) content, reduced liver cell oxidation, and reduced PSC-induced fibrosis cysts. (4) Conclusions: Our study reveals the histopathological progress of PSC infection and the cytopathogenesis of PSC-induced ferroptosis. Ferrostatin-1 effectively blocked PSCs infection and PSC-induced cell death in vivo and in vitro. Accordingly, the inhibition of PSC-induced hepatocyte ferroptosis may be an effective method in the control of Echinococcus granulosus infection and should be seriously considered in clinical studies.