Phloretin as a Multitarget Neuroprotective Agent: Mechanistic Insights into the Modulation of Oxidative Stress, Inflammation, and Apoptosis

Feb 4, 2026Neuromolecular medicine

Phloretin's protective effects on the brain by reducing oxidative stress, inflammation, and cell death

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Abstract

Neurodegenerative diseases affect millions globally and impose significant medical and economic burdens.

Neurodegenerative diseases are characterized by progressive loss of neuronal function, leading to cognitive and motor impairments.
Key mechanisms include oxidative stress, neuroinflammation, protein aggregation, and neuronal cell death.
Activation of the TLR-2/NF-κB pathway is associated with increased neuroinflammation and cell death due to excessive inflammatory cytokines.
Impairment of the TLR-2/Akt/mTOR pathway disrupts autophagy, resulting in the accumulation of α-synuclein in synucleinopathies.
Dysfunction in Nrf2-mediated antioxidant signaling may contribute to redox imbalance and neuronal apoptosis.
Phloretin, found in apples and strawberries, has potential neuroprotective effects through various biological pathways, though further studies are needed to clarify its clinical safety and efficacy.

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Neurodegenerative diseases impose a substantial and growing global burden, affecting millions worldwide and leading to high medical, social, and economic costs. These are characterized by progressive neuronal dysfunction and loss, leading to cognitive, motor, and behavioral impairments. Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease are driven by intertwined mechanisms of oxidative stress, neuroinflammation, protein aggregation, and neuronal apoptosis. Activation of the TLR-2/NF-κB axis promotes neuroinflammation and pyroptotic cell death through excessive production of pro-inflammatory cytokines, contributing to neuronal damage. Dysregulation of the TLR-2/Akt/mTOR pathway impairs autophagy, leading to defective clearance and accumulation of α-synuclein, a central event in synucleinopathies. Moreover, compromised Nrf2-mediated antioxidant signaling weakens cellular redox homeostasis and anti-apoptotic defenses, thereby linking redox imbalance to caspase-dependent neuronal apoptosis. Given the complex and multifactorial nature of neurodegenerative diseases, there is a pressing need for multitarget agents. Phloretin is a natural dihydrochalcone predominantly found in apples, pears, and strawberries. It exhibits broad pharmacological activities, including antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective effects, making it a promising multitarget phytochemical for neurodegenerative conditions. Phloretin mediates its neuroprotective properties through the modulation of several mediators, including Aβ, TLR-2, NF-κB, COX, iNOS, PPARγ, Nrf2, beclin-1, Bax, Bcl-2, caspases, PI3K/Akt, mTOR, pro-inflammatory cytokines, and antioxidant enzymes, among others. Despite compelling preclinical evidence, critical gaps remain regarding phloretin's effects on inflammasome initiation, ER stress responses, mitophagy, neurotrophic signaling, and, importantly, its clinical safety and efficacy, underscoring the need for integrated mechanistic studies and well-designed clinical trials.

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Phloretin as a Multitarget Neuroprotective Agent: Mechanistic Insights into the Modulation of Oxidative Stress, Inflammation, and Apoptosis

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