Flavonoid-mediated modulation of Tau protein: Implications for targeted therapeutics and clinical relevance in Tau-related disorders

Tau protein displays a key role in promoting tubulin assembly and microtubule stabilization. Alterations in Tau expression have been implicated in many pathologies, including neurodegenerative disorders and, more recently, certain forms of cancer such as glioblastoma, where aberrant Tau expression has been reported. The exploration and development of novel Tau-targeting agents remain in a vibrant field of research due to the urgent need for effective treatments against these Tau-dependent diseases. This review focuses on flavonoids and their role in modulating Tau function. We will begin with an overview of flavonoid classes and structures. Subsequently, we examine how flavonoids influence Tau function through both direct and indirect mechanisms, alongside key pathological Tau alterations, including liquid-liquid phase separation and aggregation. Flavonoids show promise in inhibiting Tau aggregation, but their low bioavailability limits therapeutic use. In this regard, we will outline many approaches to overcome this issue through structural modifications and nano-delivery systems to improve targeting and release of flavonoids in tissue. Finally, we highlight recent advances in the rational design of Tau-targeting agents based on flavonoid scaffolds, with particular emphasis on thiazoloflavonoids explored in GBM models. Our synthesis of current knowledge positions flavonoids as a versatile chemical platform, offering a viable path for Tau-directed therapies in neurodegenerative and oncogenic contexts. • Tau is a key target in drug discovery for many neurodegenerative disorders and cancers. • Flavonoids and their role in modulating Tau disorders from 2019 to present were reviewed. • Challenges and future directions are discussed to guide the development of new flavonoids as next-generation Tau inhibitors.