Amino AcidsL-Theanine

l-Theanine improves learning and memory in sleep-deprived mice by inhibiting NOX4-mediated ferroptosis in hippocampal neurons

l-Theanine treatment significantly increased the frequency of mice crossing the platform in the Morris water maze, indicating improved learning and memory. It also protected hippocampal neurons and mitochondria, reversed abnormal expression of ferroptosis-related proteins, and mitigated oxidative stress in HT22 cells. The neuroprotection was reversed by the GLX351322 agent, confirming the role of NOX4.

Last updated: Jul 8, 2026•0 RCTs•📖 Read as article →

Evidence Score

Evidence Score24/100
Human RCT☆☆☆☆☆
Meta-analysis☆☆☆☆☆
Mechanism★★★★★
Safety★★★★☆
Confidencelow

Study Evidence

Study 1. l-Theanine Improves Learning and Memory Through Attenuation of NOX4-Mediated Ferroptosis in Hippocampal Neurons of Sleep-Deprived Mice.

observational

Huang X, Lu X, Wu Z, Wu H, Xie Z, Cao Y · Phytotherapy research : PTR (2025)

Participants: N/A
Duration: N/A
Intervention: l-Theanine treatment in sleep-deprived mice and Erastin-induced HT22 cells
Outcome: Learning and memory (Morris water maze platform crossings), hippocampal neuron damage (Nissl staining), mitochondrial morphology (TEM), oxidative stress markers (MDA, SOD, GSH, LDH, Fe2+), ferroptosis-related protein expression (PSD-95, SYN, NOX4, TFRC, ACSL4, Nrf2, Keap1, SLC7A11, P53, HO-1, NQO1, FTH1, GPX4)
Effect Size: N/A
Population: Sleep-deprived mice and HT22 hippocampal neuronal cells

Result:

PubMed: 40682446DOI: 10.1002/ptr.70048

Mechanism Graph

Sleep deprivation increases NOX4 expression in hippocampal neurons
↓
NOX4 promotes ferroptosis via oxidative stress and iron accumulation
↓
l-Theanine attenuates NOX4 expression and downstream ferroptosis markers
↓
Result: Improved learning and memory performance in sleep-deprived mice

Limitations

  • ⚠Animal model only; human translation not established
  • ⚠Dose-response relationship not reported in abstract
  • ⚠Potential off-target effects of l-theanine not discussed

Frequently Asked Questions

What is the main mechanism by which l-theanine improves memory in sleep-deprived mice?▼

l-Theanine inhibits NOX4-mediated ferroptosis in hippocampal neurons, reducing oxidative stress and iron accumulation.

How was learning and memory measured in this study?▼

The Morris water maze was used, specifically measuring the frequency of platform crossings.

What is ferroptosis and why is it relevant to sleep deprivation?▼

Ferroptosis is an iron-dependent form of cell death involving lipid peroxidation. Sleep deprivation triggers ferroptosis in hippocampal neurons via NOX4, impairing cognitive function.

Did the study test l-theanine in humans?▼

No, this study was conducted in mice and HT22 cell lines, not in humans.

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References

  1. 1.Huang X, Lu X, Wu Z, Wu H, Xie Z, Cao Y. "l-Theanine Improves Learning and Memory Through Attenuation of NOX4-Mediated Ferroptosis in Hippocampal Neurons of Sleep-Deprived Mice.." Phytotherapy research : PTR, 2025. PMID: 40682446 DOI: 10.1002/ptr.70048
Disclaimer: This content is for educational purposes only and is not medical advice. Evidence scores reflect the quality and quantity of available research, not clinical recommendations. Always consult a healthcare professional before starting any supplement or intervention.