Flavonoids: Mechanisms and Therapeutic Potential in Multitarget Intervention forChronic Neuroinflammation

Abstract

Inflammation is a defensive response of the body to external stimuli. However, excessive or dysregulated inflammatory responses contribute to various chronic diseases, with neurodegenerative disorders accounting for approximately 30% of the global disease burden. Flavonoids are natural polyphenolic compounds widely distributed in plants. Unlike conventional anti-inflammatory drugs, which tend to induce drug resistance and cause severe side effects, these natural dietary components exhibit low toxicity, offering a safer alternative for the intervention of chronic inflammatory diseases, with particularly notable advantages in long-term therapeutic applications. Accumulating evidence indicates that they exert synergistic anti-inflammatory effects through multiple targets and pathways. In neuroinflammatory diseases, the interventional effects of these natural compounds are particularly prominent: nobiletin inhibits β-Amyloid (Aβ) aggregation via the Toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) pathway to ameliorate Alzheimer’s disease (AD) pathology; baicalin alleviates neuroinflammation through the Nuclear factor erythroid 2-related factor 2-NOD-like receptor thermal protein domain associated protein 3 (Nrf2-NLRP3) axis to protect dopaminergic neurons in Parkinson’s disease (PD) ; luteolin reduces mutant huntingtin protein aggregation to mitigate the progression of Huntington’s disease (HD) ; quercetin activates the Sestrin2/adenosine monophosphate-activated protein kinase/sirtuin 1 (Sestrin2/AMPK/SIRT1) pathway to delay motor neuron degeneration in amyotrophic lateral sclerosis (ALS) . Additionally, this review further analyzes the key challenges in the clinical translation of flavonoids, including insufficient blood-brain barrier penetration, limited bioavailability in vivo, and limitations of experimental models. To address these challenges, this review focuses on food science-oriented strategies, emphasizing two core directions: the construction of nanodelivery systems and molecular structural modification. while integrating advanced approaches such as humanized models, aiming to provide a theoretical basis and translational pathway for the clinical application of flavonoids in neuroinflammatory intervention.