Troxerutin mitigates ferroptosis-related neuroinflammation by regulating the microglial NOX4/Nrf2 axis in Parkinson's disease.
Wang Qicheng, Xu Xinyi, Liu Ziqi, Wang Ruoxun, Lan Xinrui, Li Jing, Wang Sainan, Sun Zhiyuan, Shi Liyu, Gao Yutong, Pan JiaHua, Li Wei, Qian Li
Abstract
Parkinson's disease (PD) is characterized by progressive dopaminergic neurodegeneration and chronic neuroinflammation. Increasing evidence suggests that microglial ferroptosis plays a critical role in the pathogenesis of PD. Troxerutin (TRX), a natural flavonoid derivative with potent antioxidant and anti-inflammatory activities, has shown neuroprotective potential; however, its effects on microglial ferroptosis and the underlying mechanisms in PD remain unclear. Here, we investigated the effects of TRX in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD and MPP+-stimulated BV2 cells. TRX improves motor performance, preserves nigrostriatal dopaminergic neurons, and attenuates microglial activation and pro-inflammatory cytokine expression in vivo. In BV2 cells, TRX attenuated ferroptosis-related changes, reduced lipid reactive oxygen species accumulation, and restored GPX4 and SLC7A11 expression. Furthermore, treatment with erastin, a classical ferroptosis inducer, reactivates ferroptosis-related responses and reverses the anti-inflammatory effects of TRX, linking ferroptotic stress to microglial inflammatory activation. Mechanistically, the cellular thermal shift assay supported target engagement between TRX and NOX4. TRX enhances K48-linked polyubiquitination of NOX4 and promotes its proteasomal degradation, which restores Nrf2 nuclear accumulation and activates downstream antioxidant responses. These results reveal that TRX alleviates ferroptosis-related neuroinflammation by modulating the microglial NOX4/Nrf2 axis in PD.
Key Findings
- Troxerutin (TRX) improves motor performance and preserves dopaminergic neurons in a Parkinson's disease mouse model.
- TRX attenuates microglial ferroptosis by reducing lipid ROS accumulation and restoring GPX4 and SLC7A11 expression in BV2 cells.
- TRX promotes proteasomal degradation of NOX4, restoring Nrf2 nuclear accumulation and activating antioxidant responses, thereby mitigating neuroinflammation.
Clinical Significance
Troxerutin shows potential as a therapeutic agent for Parkinson's disease by targeting microglial ferroptosis and neuroinflammation through the NOX4/Nrf2 axis, suggesting a novel approach to slow disease progression.
Citation
Wang Qicheng, Xu Xinyi, Liu Ziqiet al.. Troxerutin mitigates ferroptosis-related neuroinflammation by regulating the microglial NOX4/Nrf2 axis in Parkinson's disease. Free radical biology & medicine. 2026-Jun-06.