Oral 7,8-Dihydroxyflavone Protects Retinal Ganglion Cells by Modulating the Gut-Retina Axis and Inhibiting Ferroptosis via the Indoleacrylic Acid-AhR-ALDH1A3-FSP1 Pathway

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2025-05-14 DOI:10.1111/cns.70442

Yanping Zhou, Yifan Feng, Yingxi Zhao, Yu Wu, Min Li, Xi Yang, Xinyuan Wu, Xiangwu Chen

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Abstract

Objectives

7,8-Dihydroxyflavone (7,8-DHF) activates the TrkB receptor, offering neuroprotection, yet its pharmacological limitations restrict its safe and effective delivery to the eye and brain, impeding clinical translation. This study explores the protective effects of oral 7,8-DHF on retinal ganglion cells (RGCs) by inhibiting ferroptosis and investigates the involvement of the gut-retina axis, particularly the Indoleacrylic acid (IDA)-AhR-ALDH1A3-FSP1 pathway, with potential clinical implications.

Methods

To evaluate the neuroprotective effects of oral 7,8-DHF, retinal 3D cultures were used for axon regeneration and GCL cell apoptosis, and ONC models for RGC survival and electrophysiology. Mechanisms were investigated by assessing ferroptosis-related proteins via Western blotting, screening differential metabolites in PC12 cells, analyzing mitochondrial changes with TEM, evaluating gut microbiota shifts, and examining metabolite changes in retina and feces.

Results

Oral 7,8-DHF enhanced RGC survival and retinal function in the ONC model by inhibiting ferroptosis, independent of TrkB activation. This effect was blocked by antibiotics and AHR, ALDH1A3, and FSP1 inhibitors. Metabolomics showed increased IDA in retina and feces, with IDA inhibiting ferroptosis in PC12 cells and promoting axonal regeneration in retinal explants. Western blot revealed upregulation of nAhR and ALDH1A3, while non-FSP1 ferroptosis proteins were unaffected. 7,8-DHF also altered gut microbiota, increasing Parasutterella, which correlated with higher IDA levels.

Conclusions

7,8-DHF regulates the gut microbiota to increase IDA levels in the intestine, which subsequently leads to the accumulation of IDA in the retina. This activates the AhR-ALDH1A3-FSP1 axis in the retina, thereby inhibiting retinal ferroptosis and exerting neuroprotective effects.

Abstract Image

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口服7,8-二羟黄酮通过调节肠-视网膜轴并通过吲哚丙烯酸- ahr - aldh1a3 - fsp1途径抑制铁凋亡来保护视网膜神经节细胞

7,8-二羟黄酮（7,8- dhf）激活TrkB受体，提供神经保护，但其药理局限性限制了其安全有效地递送到眼睛和大脑，阻碍了临床转化。本研究探讨口服7,8- dhf通过抑制铁凋亡对视网膜神经节细胞（RGCs）的保护作用，并研究肠-视网膜轴，特别是吲哚丙烯酸(IDA)-AhR-ALDH1A3-FSP1通路的参与情况，具有潜在的临床意义。方法采用视网膜3D培养物进行轴突再生和GCL细胞凋亡，ONC模型进行RGC存活和电生理实验，评价口服7,8- dhf的神经保护作用。通过Western blotting评估铁中毒相关蛋白，筛选PC12细胞中的差异代谢物，用TEM分析线粒体变化，评估肠道微生物群的变化，以及检查视网膜和粪便中的代谢物变化，来研究机制。结果口服7,8- dhf通过抑制铁下垂提高ONC模型的RGC存活和视网膜功能，不依赖于TrkB激活。这种作用被抗生素和AHR、ALDH1A3和FSP1抑制剂阻断。代谢组学显示视网膜和粪便中的IDA增加，IDA抑制PC12细胞的铁下垂，促进视网膜外植体的轴突再生。Western blot显示nAhR和ALDH1A3上调，而非fsp1铁下垂蛋白未受影响。7,8- dhf也改变了肠道微生物群，增加了副菌群，这与较高的IDA水平相关。7,8- dhf调节肠道微生物群，增加肠道内的IDA水平，从而导致IDA在视网膜的积累。这激活了视网膜中的AhR-ALDH1A3-FSP1轴，从而抑制视网膜铁下垂，发挥神经保护作用。

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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.