{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T23:05:27Z","timestamp":1772060727644,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pntd.0013164","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T00:00:00Z","timestamp":1749513600000}}],"reference-count":60,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T00:00:00Z","timestamp":1748822400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013061","name":"Jilin Provincial Scientific and Technological Development Program","doi-asserted-by":"publisher","award":["20240303078NC"],"award-info":[{"award-number":["20240303078NC"]}],"id":[{"id":"10.13039\/501100013061","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013061","name":"Jilin Provincial Scientific and Technological Development Program","doi-asserted-by":"publisher","award":["YDZJ202401679ZYTS"],"award-info":[{"award-number":["YDZJ202401679ZYTS"]}],"id":[{"id":"10.13039\/501100013061","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:p><jats:italic>Clonorchis sinensis<\/jats:italic> (<jats:italic>C. sinensis<\/jats:italic>) 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 <jats:italic>C. sinensis<\/jats:italic>-induced liver lesions. Ferroptosis, a novel form of cell death involving iron overload and lipid peroxidation, exacerbates liver fibrosis; however, its role in <jats:italic>C. sinensis<\/jats:italic> infection remains unexplored. In this study, ferroptosis were detected in <jats:italic>C. sinensis<\/jats:italic>-infected C57BL\/6 mice as well as in AML12 cells stimulated by <jats:italic>C. sinensis<\/jats:italic> 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 <jats:italic>C. sinensis<\/jats:italic> 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 <jats:italic>C. sinensis-<\/jats:italic>infected mice and ESPs-stimulated AML12 cells, suggesting that ferroptosis occurred <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic>. Treatment with ferroptosis inhibitor Fer-1 in <jats:italic>C. sinensis-<\/jats:italic>infected mice alleviated ferroptosis, reduced the productions of IFN-\u03b3, TNF-\u03b1, IL-12 and IL-6, and downregulated transforming growth factor (TGF)-\u03b2\/Smad pathway activation. In AML12 cells, Fer - 1 pretreatment reduced ESPs - induced ferroptosis and IL-6, TNF-\u03b1 production. Fer - 1 also alleviated liver lesions, reduced parasite load (65%), \u03b1-SMA expression and collagen fiber deposition in infected mice. In conclusion, <jats:italic>C. sinensis<\/jats:italic> could cause ferroptosis, which promoted the secretions of IL-6 and TNF-\u03b1 as well as the activation of TGF-\u03b2\/Smad pathway, leading to exacerbated liver fibrosis.<\/jats:p>","DOI":"10.1371\/journal.pntd.0013164","type":"journal-article","created":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T18:00:25Z","timestamp":1748887225000},"page":"e0013164","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Hepatic ferroptosis induced by Clonorchis sinensis exacerbates liver 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