DC09, Derivative of 3‐(2‐hydroxy‐5‐methoxyphenyl)‐1‐(5‐methylfuran‐2‐yl)prop‐2‐en‐1‐one Attenuates Nonalcoholic Fatty Liver Disease by Targeting PI3K/Akt Pathway: Insights From In‐Vivo Zebrafish Model and In‐Vitro HepG2 Cell

Nonalcoholic fatty liver disease (NAFLD) is a progressive liver disorder characterized by lipid accumulation, oxidative stress, and inflammation, leading to severe conditions such as nonalcoholic steatohepatitis, fibrosis, or hepatocellular carcinoma. A primary driver of NAFLD is the impaired PI3K/Akt signaling pathway, which regulates lipid metabolism, glucose homeostasis, and mitochondrial function. The dysregulation of this pathway promotes lipid storage, mitochondrial damage, and hepatocyte apoptosis, critical features of NAFLD progression. Due to the lack of currently approved pharmacological treatments, the need for effective therapeutic options is being emphasized. DC09, a derivative of 3-(2-hydroxy-5-methoxyphenyl)-1-(5-methylfuran-2-yl)prop-2-en-1-one with antioxidant, anti-inflammatory, and metabolic regulatory properties, shows significant potential as a treatment for NAFLD. Additionally, molecular docking and network pharmacology revealed the ability of DC09 to stabilize key PI3K/Akt pathway proteins through strong hydrogen bonding interactions, enhancing pathway signaling. Moreover, in HepG2 cells, DC09 exhibited antiapoptotic effects by preserving mitochondrial membrane potential and reducing oxidative damage. However, zebrafish larvae studies demonstrated that DC09 significantly reduced hepatic lipid, macrophage accumulation, and triglyceride deposition. In adult zebrafish, DC09 improved systemic metabolic parameters by normalizing glucose, cholesterol, and triglyceride levels and restoring body weight. Additionally, DC09 exhibited an enhanced antioxidant enzyme, which mitigated oxidative stress and was accompanied by the downregulation of lipogenic genes, namely fasn, srebp1, and c/ebpa. Histological analysis confirmed reduced steatosis, inflammation, and cellular damage. Overall, this study emphasizes the ability of DC09 as a promising therapeutic drug against NAFLD, by targeting the PI3K/Akt pathway to alleviate hepatic and systemic manifestations of the disease.