Nobiletin

Nobiletin (NOB), a citrus peel polymethoxyflavone, is a multi-target hepatoprotective drug. NOB was taken up in the small intestine, rapidly metabolized by hepatic CYPs to generate demethylated metabolites, and primarily excreted in urine and feces. In models of acute liver injury, NOB decreased ALT/AST, inhibited oxidative stress, and attenuated inflammation. It also suppressed cytokine storms, restored antioxidant enzymes, and inhibited hepatocyte apoptosis/autophagy.
In NAFLD/NASH, NOB attenuated hepatic steatosis, dyslipidemia, insulin resistance, and fibrosis by activating PPAR-α, AMPK, SIRT1, and TFEB-mediated lipophagy and restoring circadian clock genes. It remodeled gut microbiota to enrich Allobaculum and Lactobacillus, increase short-chain fatty acids, and modulate myristoleic acid metabolism, thus improving lipid and bile-acid homeostasis. NOB also displayed antiviral effects against HBV and HCV by reducing HBsAg, HBV DNA, and viral entry. It exerted anti-HCC effects through G2/M arrest, apoptosis induction, and suppression of invasion-related ERK/PI3K/AKT signaling.

Fig. 1 Pharmacological activity and relative mechanism of Nobiletin. (Cheng Y.; et al. 2024)

Flavonoid nobiletin (NOB) was entrapped in gellan gum (GG) hydrogels by a heat-set sol-gel process. Tuning GG concentration and NaCl level effectively suppressed crystal growth to produce smaller and less-ordered crystals as evidenced by XRD and FTIR hydrogen-bonding. The composite gel possessed enhanced mechanical properties, higher viscosity, and sustained-release behavior that was markedly superior to that of pure NOB. This simple and food-grade platform provides simultaneous stabilization, protection, and controlled delivery of water-insoluble bioactives with an easily scalable strategy to improve shelf-life and bioavailability in functional foods and nutraceuticals.

Fig. 2 Hydrogel-based encapsulation of Nobiletin. (Cui B.; et al. 2023)