Journal Article

Hepatic ferroptosis induced by Clonorchis sinensis exacerbates liver fibrosis

Bao, Penglin, Yu, Yanhui, Zhang, Nan, Li, Jianhua, Zhang, Xu, Ma, Yeting, Lee, Soon-Ok, Wang, Xiaocen, Gong, Pengtao, Li, Xin, Zhang, Haoyang, Wang, Yuru

2025

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Animals / Biology and Life Sciences / Cell death / Cell Line / Clonorchiasis - parasitology / Clonorchiasis - pathology / Clonorchis sinensis - pathogenicity / Clonorchis sinensis - physiology / Disease Models, Animal / Ferroptosis / Fibrosis / Health aspects / Liver - parasitology / Liver - pathology / Liver Cirrhosis - parasitology / Liver Cirrhosis - pathology / Liver diseases / Male / Medical research / Medicine and Health Sciences / Medicine, Experimental / Mice / Mice, Inbred C57BL / NF-E2-Related Factor 2 - genetics / NF-E2-Related Factor 2 - metabolism / Phospholipid Hydroperoxide Glutathione Peroxidase - genetics / Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism / Physiological aspects / Research and Analysis Methods