Ferroptosis modulation by Toxoplasma gondii suppresses sodium iodate-driven age-related macular degeneration.

Abstract

BACKGROUND: Oxidative stress is a central driver of retinal pigment epithelium (RPE) degeneration and a defining pathological feature of age-related macular degeneration (AMD). Sodium iodate (NaIO3) is widely used to model oxidative injury in RPE cells, yet the molecular checkpoints that determine whether oxidatively stressed RPE cells succumb or survive remain poorly defined. OBJECTIVE: This study aimed to investigate whether Toxoplasma gondii (T. gondii) infection modulates NaIO3-induced oxidative stress and ferroptotic vulnerability in human RPE cells, and to elucidate the role of ferroptosis in RPE degeneration. METHODS: ARPE-19 cells were exposed to NaIO3 to induce oxidative stress and ferroptosis-associated injury, followed by infection with T. gondii. Cellular viability, cytosolic and mitochondrial reactive oxygen species (ROS), lipid peroxidation, iron homeostasis, and the expression of key ferroptosis-related regulators, including GPX4 and SLC7A11, were assessed using biochemical assays, fluorescence imaging, and immunoblotting. RESULTS: NaIO3 exposure impaired ferroptosis-associated antioxidant defenses in ARPE-19 cells by suppressing GPX4 and SLC7A11, disrupting iron homeostasis, and amplifying cytosolic and mitochondrial ROS production. T. gondii infection reversed this ferroptotic priming, markedly reduced oxidative stress, and protected RPE cells from lipid peroxidation–driven apoptotic execution. This parasite-driven cytoprotective conversion identifies ferroptosis as a pivotal regulatory node in host–pathogen interactions within the retina. CONCLUSIONS: Our findings demonstrate that T. gondii counteracts oxidative–ferroptotic stress to preserve RPE integrity, highlighting ferroptosis modulation as a key mechanism linking oxidative stress, retinal degeneration, and parasite-driven host cell reprogramming. These results expand the conceptual framework for understanding how host–pathogen interactions shape tissue vulnerability and survival in retinal disease contexts.