Flavokawain A: a multi-targeted kava chalcone with diverse therapeutic potential

Piper methysticum G. Forst., commonly known as Kava, is a culturally significant shrub native to the Pacific islands, including Fiji, Vanuatu, and Tonga. Flavokawain A is one of the primary non-kavalactone constituents found within its rhizomes. This review aims to provide a comprehensive and critical evaluation of the current state of research on Flavokawain A. Specifically, it aims to elucidate the diverse molecular mechanisms and signaling networks that drive its pharmacological effects, while assessing its viability as a multi-targeted therapeutic candidate for diverse diseases. Flavokawain A exhibits profound therapeutic potential across a spectrum of pathological conditions, including malignancy, chronic inflammation, myocardial infarction, and neurodegenerative disorders such as Alzheimer's disease. Evidence from in silico, in vitro and in vivo models suggests that Flavokawain A's efficacy is rooted in its ability to modulate key signaling hubs, notably the TGF-β1, NF-κB, PI3K/AKT, and Nrf2 pathways, as well as regulatory proteins like PRMT5, CDK2, and SKP2. These multi-target interactions underpin Flavokawain A's potent antioxidant, anti-apoptotic, and anti-inflammatory properties, positioning it as a promising candidate for multifactorial disease management. FKA represents a versatile, multi-targeted potential therapeutic scaffold with a robust pharmacological profile. Its demonstrated anti-fibrotic, anti-inflammatory, and anti-proliferative activities across diverse disease models underscore its clinical potential. However, bridging the gap from bench to bedside requires rigorous translational studies and clinical trials to validate its safety, bioavailability, and therapeutic efficacy in human populations.