Journal Article

Toxoplasma gondii-induced ferroptosis contributes to acute lung injury in mice

Liu, Feixue, Bao, Penglin, Liu, Zhenzhen, Zhang, Nan, Li, Jianhua, Ma, Yeting, Zhang, Xu, Du, Boya, Wang, Xiaocen, Yuan, Xiaodan, Gong, Pengtao, Li, Xin

2025

Overview

Background Toxoplasma gondii ( T. gondii ) is an important apicomplexan parasite that causes zoonotic toxoplasmosis in humans and animals. Acute T. gondii infection leads to systemic immunopathology that may manifest as lung injury or pulmonary embolism. Ferroptosis is an iron-dependent regulated cell death driven by lethal lipid hydroperoxide accumulation. Emerging evidence implicates ferroptosis in infection-related tissue damage; however, the role of ferroptosis in T. gondii -induced lung injury remains to be explored. Methods Mice were infected with T. gondii to establish a lung injury model. The body weight changes, survival rate, inflammatory cytokines, lung histopathology, and parasite burden were assessed. The key ferroptosis-related indicators involved in antioxidant, iron metabolism, and lipid metabolism pathways were analyzed in lung tissues using techniques such as transmission electron microscopy, western blotting, and immunohistochemistry. Deferiprone (DFP), an oral iron chelator that can inhibit ferroptosis, was used to investigate the potential role of ferroptosis in T. gondii lung injury. Results T. gondii infection induced lung injury in mice with thickening of alveolar septa and hemorrhage in alveolar spaces, accompanied by iron deposition. Crucially, T. gondii triggered ferroptosis in lung tissues of mice, evidenced by MDA elevation, GSH depletion, total iron and Fe 2+ overload, and mitochondrial cristae loss. Furthermore, iron metabolism pathways were disordered while antioxidant pathways were suppressed. DFP treatment reversed ferroptosis alterations, decreased inflammatory cytokines, attenuated pathological changes, reduced T. gondii burden, and prolonged survival of the infected mice. Conclusions Our findings revealed that T. gondii infection triggered ferroptosis by compromising dysregulated iron metabolism and antioxidant defenses, playing a key role in T. gondii -induced lung injury. DFP exhibited a promising therapy effect for toxoplasmosis. Graphical Abstract

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Acute Lung Injury - parasitology / Acute Lung Injury - pathology / Alveoli / Animal tissues / Animals / Antioxidant / Antioxidants / Biomedical and Life Sciences / Biomedicine / Body weight / Cell death / chelating agents / Cristae / Cytokines / Cytokines - metabolism / Deferiprone / Disease Models, Animal / Electron microscopy / Embolism / Encephalitis / Entomology / Female / Ferroptosis / Fluorides / Glutathione / Haemorrhage / Health aspects / Hemorrhage / Histopathology / Immunohistochemistry / immunopathology / Infection / Infections / Infectious Diseases / Inflammation / Injuries / Iron / Iron - metabolism / iron absorption / Lipid metabolism / lipid peroxides / Lipids / Liver / Lung - parasitology / Lung - pathology / Lung injury / Lungs / Medical research / Medicine, Experimental / Membranes / Metabolism / Mice / mitochondria / Oxidative stress / Parasites / Parasitology / Physiological aspects / Proteins / Protozoa / Pulmonary embolism / Survival / Survival analysis / survival rate / therapeutics / Tissue / Toxoplasma - pathogenicity / Toxoplasma - physiology / Toxoplasma gondii / Toxoplasmosis / Toxoplasmosis - parasitology / Toxoplasmosis, Animal - parasitology / Toxoplasmosis, Animal - pathology / Transmission electron microscopy / Tropical Medicine / Tuberculosis / Tumor necrosis factor-TNF / Veterinary Medicine/Veterinary Science / Virology / Western blotting