Urolithin A reverses sleep deprivation-induced cognitive decline and anxiety by blocking hippocampal ferroptosis
Urolithin A (UA), a gut-microbiota-derived metabolite of ellagitannins found in pomegranates and berries, prevents the cognitive impairments and anxiety-like behaviors caused by chronic sleep deprivation in mice by suppressing iron-dependent cell death (ferroptosis) in the hippocampus, researchers report in Phytomedicine.
The study identifies the Nrf2 antioxidant signaling pathway as the key molecular mechanism, opening a potential avenue for nutritional interventions targeting sleep-loss-related brain injury.
What they found
Wang and colleagues from Yan’an University, Chengdu University of TCM, and the Fourth Military Medical University subjected mice to 14 consecutive days of sleep restriction and treated them with UA (100 mg/kg intragastric).
Behavioral testing showed that UA significantly mitigated cognitive deficits and anxiety-like behaviors caused by chronic sleep deprivation. Histological examination revealed that UA prevented hippocampal neuron damage, reduced excessive neuroinflammation, and increased dendritic spine density and neurotrophic factor protein levels.
Using spatial metabolomics and functional network analysis, the team traced the protective mechanism to the Nrf2-ferroptosis axis. In the hippocampus of UA-treated mice:
- Total iron and ferrous iron (Fe2+) levels were significantly reduced.
- Nrf2 protein and its downstream targets SLC7A11, GPX4, and HMOX1 were upregulated.
- ACSL4, a pro-ferroptosis marker, was downregulated.
In vitro validation using HT-22 hippocampal cells confirmed the pathway: UA protected cells from erastin-induced ferroptosis in a dose-dependent manner (2.5-10 μM), and this protection was completely abolished by the Nrf2 inhibitor ML385.
Why it matters
Chronic sleep deprivation is associated with hippocampal atrophy, cognitive decline, and mood disturbances in humans, but the molecular mechanisms linking sleep loss to neuronal damage have remained unclear. The identification of ferroptosis, an iron-dependent form of regulated cell death, as a driver of sleep-deprivation-induced brain injury provides a concrete molecular target.
Urolithin A is already of interest in aging research for its role in mitophagy and mitochondrial health. This study adds sleep-related neuroprotection to its potential benefits, though the work is at the preclinical stage.
Limits
These results come from a mouse model. Whether oral UA supplementation at achievable human doses can produce similar effects on sleep-deprivation-induced cognitive impairment remains unknown. The 14-day continuous sleep restriction paradigm also does not perfectly model the intermittent or partial sleep deprivation patterns typical in human populations.
Bottom line
Urolithin A prevents cognitive decline and anxiety from chronic sleep deprivation in mice by activating Nrf2 signaling and suppressing hippocampal ferroptosis, providing a molecular framework for nutritional strategies to mitigate sleep-loss-related brain injury.
Source: Wang W, Ding Y, Qingji R, Zhang Y. Urolithin A supplementation improves chronic sleep deprivation-induced cognitive impairments and anxiety in mice by suppressing hippocampal ferroptosis via the Nrf2 signaling. Phytomedicine. 2026;159:158497. DOI: 10.1016/j.phymed.2026.158497