Activity-based sensing reveals elevated labile copper promotes liver aging via hepatic ALDH1A1 depletion

Zhenxiang Zhao, Melissa Y. Lucero, Shengzhang Su, Eric J. Chaney, Jiajie Jessica Xu, Michael Myszka and Jefferson Chan ()
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Zhenxiang Zhao: University of Illinois Urbana-Champaign
Melissa Y. Lucero: University of Illinois Urbana-Champaign
Shengzhang Su: University of Illinois Urbana-Champaign
Eric J. Chaney: University of Illinois Urbana-Champaign
Jiajie Jessica Xu: University of Illinois Urbana-Champaign
Michael Myszka: University of Illinois Urbana-Champaign
Jefferson Chan: University of Illinois Urbana-Champaign

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract Oxidative stress plays a key role in aging and related diseases, including neurodegeneration, cancer, and organ failure. Copper (Cu), a redox-active metal ion, generates reactive oxygen species (ROS), and its dysregulation contributes to aging. Here, we develop activity-based imaging probes for the sensitive detection of Cu(I) and show that labile hepatic Cu activity increases with age, paralleling a decline in ALDH1A1 activity, a protective hepatic enzyme. We also observe an age-related decrease in hepatic glutathione (GSH) activity through noninvasive photoacoustic imaging. Using these probes, we perform longitudinal studies in aged mice treated with ATN-224, a Cu chelator, and demonstrate that this treatment improves Cu homeostasis and preserves ALDH1A1 activity. Our findings uncover a direct link between Cu dysregulation and aging, providing insights into its role and offering a therapeutic strategy to mitigate its effects.

Date: 2025
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DOI: 10.1038/s41467-025-56585-4

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