Hepatic ferroptosis induced by Clonorchis sinensis exacerbates liver fibrosis.
Clonorchis sinensis (C. sinensis) is a food-borne zoonotic parasite link to liver fibrosis and cholangiocarcinoma. Limited understanding of its mechanisms in causing liver fibrosis has impeded therapeutic advances for C. sinensis-induced liver lesions. Ferroptosis, a novel form of cell death involvi...
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| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2025-06-01
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| Series: | PLoS Neglected Tropical Diseases |
| Online Access: | https://doi.org/10.1371/journal.pntd.0013164 |
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| Summary: | Clonorchis sinensis (C. sinensis) is a food-borne zoonotic parasite link to liver fibrosis and cholangiocarcinoma. Limited understanding of its mechanisms in causing liver fibrosis has impeded therapeutic advances for C. sinensis-induced liver lesions. Ferroptosis, a novel form of cell death involving iron overload and lipid peroxidation, exacerbates liver fibrosis; however, its role in C. sinensis infection remains unexplored. In this study, ferroptosis were detected in C. sinensis-infected C57BL/6 mice as well as in AML12 cells stimulated by C. sinensis excretory/secretory products (ESPs). 12 ferroptosis related genes were screened and we found glutathione peroxidase 4 (GPX4, 7 d), solute carrier family 7 member 11 (SLC7A11, 7 d) and nuclear factor erythroid 2 related factor 2 (Nrf2, 35 d) was significantly decreased in mice. Western blot results confirmed C. sinensis and ESPs down-regulated the expression of GPX4, SLC7A11 and Nrf2. GSH depletion, malondialdehyde (MDA) accumulation, mitochondrial structure damage, and iron overload were found in C. sinensis-infected mice and ESPs-stimulated AML12 cells, suggesting that ferroptosis occurred in vivo and in vitro. Treatment with ferroptosis inhibitor Fer-1 in C. sinensis-infected mice alleviated ferroptosis, reduced the productions of IFN-γ, TNF-α, IL-12 and IL-6, and downregulated transforming growth factor (TGF)-β/Smad pathway activation. In AML12 cells, Fer - 1 pretreatment reduced ESPs - induced ferroptosis and IL-6, TNF-α production. Fer - 1 also alleviated liver lesions, reduced parasite load (65%), α-SMA expression and collagen fiber deposition in infected mice. In conclusion, C. sinensis could cause ferroptosis, which promoted the secretions of IL-6 and TNF-α as well as the activation of TGF-β/Smad pathway, leading to exacerbated liver fibrosis. |
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| ISSN: | 1935-2727 1935-2735 |