Mechanistic and therapeutic strategies to mitigate arsenic trioxide-induced neurotoxicity - arsenic trioxide (ATO) is a widely used chemical in industry, healthcare, and warfare, imported in large…

The National Institutes of Health Office of the Director awarded the University of Tennessee Health Science Center $403,972 under the Trans-NIH Research Support program (CFDA 93.310) on August 15, 2026, to define mechanistic pathways through which arsenic trioxide disrupts brain and cognitive function and to identify novel therapeutic strategies to prevent or mitigate delayed neurotoxic consequences of exposure. Research focuses on the integrated stress response and stimulator of interferon genes signaling pathways as key drivers of arsenic trioxide-induced neurodegeneration, building on prior transcriptomic and molecular profiling that identified these mechanisms as central to how the chemical elevates serum heme levels and triggers stress responses in human induced pluripotent stem cell-derived neurons and mouse brains. The award period runs through July 31, 2029, with performance in Memphis, Tennessee.

Mechanistic and therapeutic strategies to mitigate arsenic trioxide-induced neurotoxicity - arsenic trioxide (ATO) is a widely used chemical in industry, healthcare, and warfare, imported in large quantities in the united states. As a highly toxic hemolytic agent, ATO poses significant risks of accidental release during industrial accidents, deliberate attacks, or terrorist incidents and is therefore classified as a chemical of concern (COC). Epidemiological studies link ATO exposure to cognitive impairment and an increased risk of alzheimer's disease (ad)-related dementia, and preclinical studies consistently show that ATO promotes the onset and progression of ad-like neurodegeneration. Despite these associations, the cellular and molecular mechanisms driving delayed ATO-induced neurotoxicity remain undefined, and the brain regions and cell populations most vulnerable to its effects are unknown. IT is also unclear whether ATO further elevates dementia risk in individuals harboring deleterious genetic variants that confer high susceptibility. Critically, no effective medical countermeasures exist to prevent or mitigate the delayed cognitive and neurotoxic consequences of ATO. Our proposal addresses this GAP by defining the mechanistic pathways through which ATO disrupts brain and cognitive function and by identifying novel therapeutic strategies, directly responding to PAR-25-077. Building on our comprehensive transcriptomic and molecular profiling, we identified the integrated stress response (ISR) and the stimulator of interferon genes (sting) immune pathway as key drivers of ATO- induced neurotoxicity. The ISR is a conserved adaptive pathway that regulates protein translation, and its dysregulation contributes to neural and systemic disease. Consistent with its hemolytic properties, ATO elevates serum heme levels, and triggers ISR activation in human ipsc-derived neurons and in WT mouse brains. Concurrently, ATO activates sting signaling in human ipsc-derived microglia and mouse brain, converging to drive neuroinflammation and cognitive deficits. We hypothesize that ATO-induced heme release activates ISR signaling in the brain, which contributes to cognitive and functional impairments through dysregulated sting- mediated immune responses, and that modulation of the ISR-sting axis can alleviate ATO-induced neurotoxicity. To test this, we propose two specific aims. In aim 1, we will determine how ATO triggers ISR signaling to drive behavioral and cognitive deficits in both healthy and genetically susceptible mice, and in aim 2, we will elucidate the molecular mechanisms by which ISR-sting cross-talk mediates neurotoxicity and cognitive dysfunction. This project employs innovative and integrative approaches, combining human ipsc- derived neurons and microglia with novel conditional mouse models and cutting-edge molecular techniques, including spatial transcriptomics, to map region- and cell-specific transcriptional responses. These approaches will transform our understanding of ATO-induced neurotoxicity by revealing how neuronal stress and immune pathways intersect, establishing the ISR-sting axis as a critical, druggable target, and paving the way for transformative interventions to prevent or reverse delayed cognitive and neurotoxic effects.