Herbacetin Inhibits Human Fructose 1,6‐Bisphosphatase Among a Panel of Chromone Derivatives and Pyrazoles, Demonstrating Positive Effects on Insulin‐Resistant HepG2 Cells

ABSTRACT

In patients with type 2 diabetes mellitus (DM), excessive gluconeogenesis is considered a major contributor to hyperglycemia. Therefore, targeting fructose 1,6‐bisphosphatase (FBPase), a key regulatory enzyme involved in gluconeogenesis, has gained interest as a potential therapeutic target for managing DM. In this study, a library of 42 structurally‐related chromone derivatives (including flavonoids, 2‐styrylchromones, and 2‐(4‐arylbuta‐1,3‐dien‐1‐yl)chromones, named as 2‐styrylchromone‐related derivatives), as well as 4‐ and 5‐styrylpyrazoles, were tested against human FBPase using a noncellular microanalysis screening system. Herbacetin, 3,4′,5,7,8‐pentahydroxyflavone, inhibited FBPase activity with an IC₅₀ value of 6.4 ± 0.7 μM. The effects of herbacetin were also explored using an insulin‐resistant human hepatocellular carcinoma cell line (HepG2 cells). The results showed that herbacetin significantly decrease insulin resistance by promoting the phosphorylation of protein kinase B (Akt), and exhibited a capacity to ameliorate inflammation, evidenced by the modulation of the inhibitor of κB alpha (IκBα). This study provides important considerations for the design of novel FBPase inhibitors. Furthermore, it indicates a preliminary potential of herbacetin's dual action in improving insulin resistance and decreasing inflammation, suggesting the need for further investigation of this compound for addressing the complexities of type 2 DM management.