Amino AcidsL-Theanine

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

In sleep-deprived mice, l-theanine treatment significantly increased the frequency of 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 (e.g., NOX4, GPX4, ACSL4), and mitigated oxidative stress in HT22 cells. The neuroprotective effects were reversed by the GLX351322 agent, confirming the role of NOX4 inhibition.

Last updated: Jul 7, 2026•0 RCTs•📖 Read as article →

Evidence Score

Evidence Score26/100
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 upregulation promotes ferroptosis via oxidative stress and iron accumulation
↓
l-Theanine attenuates NOX4 expression, reducing ferroptosis markers (e.g., GPX4, SLC7A11, FTH1)
↓
Result: Improved learning and memory in sleep-deprived mice

Limitations

  • ⚠Dosage of l-theanine not specified in abstract, limiting translational applicability
  • ⚠Study conducted in animal models (mice and cell lines), not in humans
  • ⚠Mechanism focused on NOX4 pathway; other potential pathways not explored

Frequently Asked Questions

What is the main finding of this study?▼

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

How was learning and memory measured?▼

Using the Morris water maze (MWM) test, specifically the frequency of crossing the platform.

What is ferroptosis and why is it relevant?▼

Ferroptosis is an iron-dependent form of cell death involving oxidative stress. The study shows that sleep deprivation triggers ferroptosis in hippocampal neurons via NOX4, and l-theanine blocks this process.

Could l-theanine be used for human sleep deprivation?▼

This is an animal study, so human trials are needed. However, l-theanine is known for its antioxidative properties and is already used as a supplement.

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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.