Natural Flavonoids as Ferroptosis Inhibitors in CNS Diseases

Introduction to Ferroptosis and Its Role in CNS Diseases

Ferroptosis is a form of regulated cell death characterized by the accumulation of lipid peroxides and is driven by iron-dependent mechanisms. Unlike apoptosis, ferroptosis does not involve caspases and is distinguished by its unique morphological and biochemical features, including mitochondrial shrinkage and increased membrane density without swelling (Dixon et al., 2012). This pathway has garnered significant attention for its role in central nervous system (CNS) diseases, where ferroptosis contributes to neuronal death in conditions such as ischemic stroke, traumatic brain injury, and neurodegenerative disorders (Hu et al., 2024).

The CNS is particularly vulnerable to oxidative stress and lipid peroxidation due to its high lipid content and relatively low levels of antioxidant defense systems. Consequently, the dysregulation of iron metabolism and antioxidant pathways in the CNS can exacerbate neuronal damage, underscoring the importance of identifying therapeutic strategies aimed at inhibiting ferroptosis (Zhang et al., 2024). Recent research has highlighted the potential of natural flavonoids—plant-derived polyphenolic compounds—to serve as effective ferroptosis inhibitors, offering a promising avenue for neuroprotection in CNS diseases (Li et al., 2025).

Mechanisms of Ferroptosis in Central Nervous System Disorders

Ferroptosis is primarily mediated by three interrelated processes: lipid peroxidation, iron overload, and antioxidant system dysfunction. Each of these processes contributes to the pathogenesis of CNS diseases and can be targeted therapeutically.

Lipid Peroxidation

Lipid peroxidation involves the oxidative degradation of polyunsaturated fatty acids (PUFAs) in cell membranes, resulting in the formation of reactive lipid peroxides (L-OOHs). This process is catalyzed by reactive oxygen species (ROS) and is exacerbated by iron overload, leading to cell membrane damage and ultimately inducing ferroptosis (Dixon and Olzmann, 2024). Elevated levels of L-OOHs can trigger a cascade of cellular damage, disrupting essential cellular functions and contributing to the progression of neurodegenerative diseases (Hu et al., 2022).

Iron Overload

Iron plays a dual role in cellular metabolism; while it is essential for various biological processes, excess iron can catalyze the Fenton reaction, producing harmful hydroxyl radicals that initiate lipid peroxidation (Rouault, 2013). In the context of CNS disorders, iron accumulation can occur due to disruptions in iron homeostasis, leading to increased cellular oxidative stress and neuronal death (Zhang et al., 2024). Studies indicate that the regulation of iron uptake (via transferrin receptor, TfR) and export (via ferroportin, FPN) is crucial in preventing ferroptosis in neuronal cells (Chen et al., 2024).

Antioxidant System Dysfunction

The cellular antioxidant defense system, primarily mediated by glutathione (GSH) and glutathione peroxidase 4 (GPX4), plays a vital role in preventing ferroptosis. The System Xc−/GSH/GPX4 axis is responsible for maintaining redox balance and facilitating the reduction of lipid peroxides (Chen et al., 2021b). Dysregulation of this antioxidant system due to oxidative stress or inflammation can lead to decreased GSH levels and impaired GPX4 activity, promoting ferroptosis and neuronal injury in CNS diseases (Zhang et al., 2021d).

Key Natural Flavonoids and Their Effects on Ferroptosis

Natural flavonoids, widely recognized for their antioxidant properties, have been shown to inhibit ferroptosis through multiple mechanisms. Some key flavonoids with neuroprotective effects include:

1. Baicalin and Baicalein: These flavonoids, derived from the roots of Scutellaria baicalensis, have demonstrated significant neuroprotective effects in preclinical models of CNS injuries, such as ischemic stroke and traumatic brain injury. They exert their effects by activating the Nrf2/ARE pathway, modulating iron metabolism, and enhancing GPX4 activity (Li et al., 2025).

2. Quercetin: Known for its antioxidant and anti-inflammatory properties, quercetin has been shown to reduce ferroptosis-induced neuronal death in vitro and in vivo by decreasing iron accumulation and enhancing the expression of antioxidant enzymes (Zhang et al., 2024).

3. Chrysin: This flavonoid has been reported to inhibit ferroptosis by reducing lipid peroxidation and increasing GSH levels, thereby protecting neurons from oxidative stress (Li et al., 2025).

4. Isoquercetin: As a glycosylated form of quercetin, isoquercetin shows enhanced bioavailability and has been linked to anti-ferroptotic effects in various neurodegenerative disease models (Li et al., 2025).

5. Eriodictyol: This flavonoid has been identified as a potent ferroptosis inhibitor, acting through antioxidant pathways and iron chelation mechanisms (Li et al., 2025).

Table 1: Summary of Key Natural Flavonoids and Their Effects on Ferroptosis

Preclinical Evidence Supporting Flavonoids in Treating CNS Diseases

Numerous preclinical studies have demonstrated the efficacy of natural flavonoids in treating various CNS conditions through inhibition of ferroptosis. For instance, animal models of ischemic stroke have shown that administration of baicalin significantly reduces infarct size and improves neurological outcomes by enhancing GPX4 expression and modulating iron homeostasis (Li et al., 2025). Similarly, quercetin has been reported to mitigate oxidative stress and neuronal death in models of Alzheimer’s disease, highlighting its potential as a therapeutic agent for neuroprotection (Zhang et al., 2024).

In the context of traumatic brain injury, flavonoid treatments have been associated with decreased lipid peroxidation and improved cognitive function. Studies have indicated that flavonoids like chrysin and eriodictyol can effectively reduce neuronal loss and promote recovery following acute injuries (Li et al., 2025).

Table 2: Overview of Preclinical Evidence Supporting Flavonoids

Future Perspectives on Flavonoids as Therapeutic Agents

The therapeutic potential of natural flavonoids as ferroptosis inhibitors in CNS diseases is promising, yet several challenges remain. Future research should focus on the following areas to enhance clinical applicability:

1. Pharmacokinetics and Bioavailability: Understanding the pharmacokinetics of flavonoids is crucial for optimizing their therapeutic use. Modifications to improve bioavailability and stability in the bloodstream can enhance their efficacy as ferroptosis inhibitors.

2. Mechanistic Studies: Further investigations into the molecular mechanisms by which flavonoids exert their neuroprotective effects will provide insights into their potential synergistic roles with existing therapies (Li et al., 2025).

3. Clinical Trials: Conducting well-designed clinical trials will be essential to evaluate the safety and efficacy of flavonoid treatments in patients with CNS diseases, particularly in the context of acute injuries and chronic neurodegenerative conditions.

4. Combination Therapies: Exploring the use of flavonoids in combination with other therapeutic agents may enhance their neuroprotective effects and improve outcomes in CNS diseases.

FAQ Section

What are flavonoids?
Flavonoids are a class of naturally occurring polyphenolic compounds found in various fruits, vegetables, and beverages, known for their antioxidant and anti-inflammatory properties.

How do flavonoids inhibit ferroptosis?
Flavonoids inhibit ferroptosis by reducing lipid peroxidation, modulating iron metabolism, and enhancing antioxidant defenses, particularly through the activation of the Nrf2/ARE pathway.

What CNS diseases are associated with ferroptosis?
Ferroptosis is implicated in several CNS diseases, including ischemic stroke, traumatic brain injury, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease.

Are there any side effects of flavonoid treatments?
While flavonoids are generally considered safe, potential side effects can vary depending on the specific flavonoid and dosage. It is important to consult healthcare professionals before starting any new treatment.

What is the significance of preclinical studies on flavonoids?
Preclinical studies provide essential insights into the efficacy and mechanisms of flavonoids as potential therapeutic agents, paving the way for future clinical trials and applications in medical settings.

References

1. Dixon, S. J., & Olzmann, J. A. (2024). Ferroptosis: An iron-dependent form of cell death. Nature Reviews Molecular Cell Biology, 25(3), 144-162

2. Hu, L., Zhang, Y., Xu, Z., & Wang, W. (2022). Ferroptosis in central nervous system diseases: A systematic review. Frontiers in Pharmacology, 13, 107453

3. Li, Q., Yang, X., & Li, T. (2025). Natural flavonoids from herbs and nutraceuticals as ferroptosis inhibitors in central nervous system diseases: Current preclinical evidence and future perspectives. Frontiers in Pharmacology, 15, e1570069. DOI: https://doi.org/10.3389/fphar.2025.1570069

4. Zhang, S. & Yang, X. (2024). The role of flavonoids in neuroprotection: A focus on ferroptosis. Journal of Neuroinflammation, 21(1), 1-15