5-Demethylnobiletin: Insights into its pharmacological activity, mechanisms, pharmacokinetics and toxicity

5-Demethylnobiletin (5DN) is a polymethoxyflavone (PMF) primarily found in citrus fruits. It has various health-promoting properties and hence has attracted significant attention from scholars worldwide.This review is the first to systematically summarize the recent research progress of 5DN, including its pharmacological activity, mechanism of action, pharmacokinetics, and toxicological effects. In addition, the pharmacological mechanism of action of 5DN has been discussed from a molecular biological perspective, and data from in vivo and in vitro animal studies have been compiled to provide a more thorough understanding of 5DN as a potential lead drug.Data were extracted from SciFinder, PubMed, ScienceDirect and China National Knowledge Infrastructure (CNKI) from database inception to January 2022.5DN has broad pharmacological activities. It exerts anti-inflammatory effects, promotes apoptosis and autophagy, and induces melanogenesis mainly by regulating the JAK2/STAT3, caspase-dependent apoptosis, ROS-AKT/mTOR, MAPK and PKA-CREB signaling pathways. 5DN can be used for treating diseases such as cancer, inflammation-related diseases, rheumatoid arthritis, and neurodegenerative diseases. To date, there have been only a few toxicological studies on 5DN, and both in vitro and in vivo on 5DN have not revealed significant toxic side effects. Pharmacokinetic studies have revealed that the metabolites of 5DN are mainly 5,3'-didemethylnobiletin (M1); 5,4'-didemethylnobiletin (M2) and 5,3',4'-tridemethylnobiletin (M3), in either, glucuronide-conjugated or monomeric form. The pharmacokinetic products of 5DN, especially M1, possess better activity than 5DN for the treatment of cancer.The anticancer effects of 5DN and its metabolites warrant further investigation as potential drug candidates, especially through in vivo studies. In addition, the therapeutic effects of 5DN in neurodegenerative diseases should be examined in more experimental models, and the absorption and metabolism of 5DN should be further investigated in vivo.