Epigenetic regulators polyphenols in neurodegenerative diseases: a promising intervention strategy

Neurodegenerative diseases are complex disorders characterized by the progressive loss of neuronal structure and function, involving pathological mechanisms such as oxidative stress, chronic inflammation, protein misfolding, and impaired synaptic plasticity. Recent studies have revealed that epigenetic regulation plays a critical role in the onset and progression of these diseases, including mechanisms such as DNA methylation, histone modifications, and non-coding RNA regulation. Natural polyphenolic compounds, known for their safety and multi-target properties, have emerged as promising candidates for neuroprotection and therapeutic intervention.

This review summarizes recent advances in the neuroprotective effects of polyphenols in neurodegenerative diseases through epigenetic mechanisms. It focuses on their regulation of DNA methyltransferase activity, histone acetylation status, and non-coding RNA expression, as well as their influence on neurotrophic factors, inflammatory mediators, and synapse-related gene expression.

Polyphenolic compounds such as curcumin, resveratrol, and epigallocatechin gallate (EGCG) have been shown to modulate epigenetic enzyme activity, alleviate neuroinflammation, improve mitochondrial function, and promote neuroregeneration, demonstrating multi-level neuroprotective effects. However, clinical translation is limited by low oral bioavailability, rapid metabolism, and insufficient brain-targeting capacity. Emerging strategies including nano-delivery systems, prodrug design, and omics technologies hold promise in overcoming these limitations and enhancing therapeutic efficacy.

Polyphenols exert multi-target regulatory effects via epigenetic mechanisms in neurodegenerative diseases, showing great potential for intervention. In the future, integrating precision nutrition, personalized treatment, and multi-omics approaches may facilitate the development of novel epigenetic-based strategies for the prevention and treatment of neurodegenerative disorders.