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Troxerutin mitigates ferroptosis-related neuroinflammation by regulating the microglial NOX4/Nrf2 axis in Parkinson's

Qicheng Wang1, Xinyi Xu1, Ziqi Liu1

  • 1Key Laboratory of the Jiangsu Higher Education Institutions for Nucleic Acid & Cell Fate Regulation (Yangzhou University), Faculty of Medicine, Yangzhou University, Yangzhou, Jiangsu, 225001, PR China.

Free Radical Biology & Medicine
|June 7, 2026
PubMed

Insights

Troxerutin (TRX) alleviates Parkinson's disease (PD) symptoms by reducing microglial ferroptosis and neuroinflammation. It achieves this by targeting the NOX4/Nrf2 pathway, offering a potential therapeutic strategy for PD.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Immunology

Background:

  • Parkinson's disease (PD) involves dopaminergic neurodegeneration and neuroinflammation.
  • Microglial ferroptosis is increasingly implicated in PD pathogenesis.
  • The neuroprotective effects and mechanisms of Troxerutin (TRX) in PD, particularly concerning microglial ferroptosis, are not fully understood.

Purpose of the Study:

  • To investigate the therapeutic effects of Troxerutin (TRX) on a mouse model of Parkinson's disease (PD).
  • To elucidate the mechanisms by which TRX affects microglial ferroptosis and neuroinflammation in PD.

Main Methods:

  • Utilized a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD and MPP+-stimulated BV2 microglial cells.
  • Assessed motor performance, dopaminergic neuron survival, microglial activation, and pro-inflammatory cytokine levels.
  • Analyzed ferroptosis markers, lipid reactive oxygen species, and expression of GPX4 and SLC7A11.
  • Employed cellular thermal shift assay to identify TRX targets and investigated protein ubiquitination and degradation pathways.

Main Results:

  • TRX improved motor function, protected nigrostriatal dopaminergic neurons, and reduced microglial activation and inflammation in vivo.
  • In vitro, TRX mitigated ferroptosis, decreased lipid ROS, and restored GPX4 and SLC7A11 expression.
  • TRX was found to engage with NOX4, promoting its degradation via K48-linked polyubiquitination, leading to Nrf2 nuclear accumulation and antioxidant response activation.
  • Erastin-induced ferroptosis reversed TRX's anti-inflammatory effects, confirming the link between ferroptosis and microglial inflammation.

Conclusions:

  • Troxerutin (TRX) demonstrates significant neuroprotective effects in a mouse model of Parkinson's disease (PD).
  • TRX alleviates neuroinflammation by inhibiting microglial ferroptosis through the modulation of the NOX4/Nrf2 signaling pathway.
  • TRX represents a promising therapeutic agent for PD by targeting ferroptosis-related neuroinflammation.
Keywords:
FerroptosisNOX4NeuroinflammationParkinson's diseaseTroxerutin

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