Targeting Ferroptosis with Natural Products: A Promising Strategy for Neurodegenerative Diseases.

Neurodegenerative diseases (NDDs) are chronic disorders characterized by progressive neuronal damage, neuronal loss, and gradual decline in neural function. They commonly present with cognitive impairment or motor dysfunction, seriously reducing patients' quality of life. Ferroptosis is a form of cell death marked by excessive iron accumulation, lipid peroxidation (LPO), and disrupted anti-oxidant defenses. It can aggravate neuronal injury and contributes to the onset and progression of NDDs. This paper reviews recent advances in the neuroprotective effects of natural compounds through ferroptosis regulation. Based on recent cellular and animal studies on natural compounds, ferroptosis, and neuronal damage, we summarized the pharmacological features and potential mechanisms of phenethyl glycosides, polyphenols, flavonoids, and other natural compounds. Available evidence shows that natural compounds, including salidroside (SAL), forsythoside A (FA), syringin, tenuifolin (Ten), tannic acid (TA), eriodictyol, quercetin (QCT), epigallocatechin-3-gallate (EGCG), emodin, and Herpotrichone A (He-A), can alleviate neuronal injury to varying extents by reducing abnormal iron accumulation. Some compounds also suppress ferroptosis by modulating intracellular anti-oxidant defense pathways and restoring glutathione (GSH)-related protective enzyme functions. Overall, natural products offer the advantage of multi-target and multi-step intervention in neural injury and show great potential for delaying neurodegeneration progression. However, current evidence mainly comes from cell and animal studies, while clinical research remains limited. Moreover, some compounds still face problems such as low bioavailability and incompletely understood mechanisms. Future studies should strengthen clinical translation and validation, clarify safety, effective dosages, and targets, and improve clinical applicability through strategies such as structural optimization.