Pharmacological activities and mechanistic insights of justicidin variants: a multi-target natural lignans

Justicidins are naturally occurring arylnaphthalene lignans found mainly in Justicia species, with documented anticancer, anti-inflammatory, antiviral, neuroprotective, and cardioprotective activities. They target several biochemical pathways, such as NF-κB, MAPK, and PI3K/Akt/mTOR, and have the potential to serve as multi-target drugs for complex diseases. Although there have been several in vitro and in vivo studies, most remain preclinical and isolated, with little consideration of structure-activity relationships, pharmacokinetics, and translational relevance. This review provides a pathway-centric, integrative review of justicidins, links structures to activities, pharmacokinetic and toxicological properties of analogues, and explores synergy with current drugs. We also discuss developments in analytical, biosynthetic, and formulation that might expedite drug discovery. However, key challenges include low water solubility, low bioavailability, the absence of chronic toxicity studies, and a lack of clinical trials. To overcome these challenges, it is important to focus on optimization, GMP production, chronic toxicity evaluation, and early clinical evaluation. With focused development, justicidins have the potential to go from natural products to therapeutic leads against cancer, inflammation, and viral infections.