Dendrobine通过调控Wnt5a/p-CaMKII/p-Drp1信号轴抑制线粒体裂变改善非酒精性脂肪性肝病

Abstract

Ethnopharmacological relevance Dendrobium nobile Lindl. (DNL) is a precious traditional Chinese herbal medicine with a variety of bioactive substances, which is recorded in the Chinese Pharmacopoeia (2025 edition). Contemporary pharmacological research has demonstrated that DNL possesses the functions of enhancing immune function, regulating the gastrointestinal tract, resisting liver injury and lowering blood sugar levels. Recently, dendrobine (DDB), the principal bioactive component of DNL, has been identified to exhibit hepatoprotective effects. However, the therapeutic effects and mechanisms of DDB in the context of non-alcoholic fatty liver disease (NAFLD) remain largely unexplored. Aim of the study The aim of this study was to investigate the role of mitochondrial fission in the model of high-fat diet (HFD) and palmitic acid (PA)-induced NAFLD and determine whether DDB protects against NAFLD by inhibiting dynamin-related protein 1 (Drp1)-mediated mitochondrial fission. Materials and methods In this study, NAFLD models in vivo and in vitro were established in C57BL/6J mice and AML12 cells through HFD and PA, respectively. Animal ultrasound, hepatic histopathological examination and serum biochemical analysis were employed to evaluate liver fat accumulation and damage. RNA-sequencing was conducted to explore the changes in gene expression in NAFLD. Transmission electron microscope, ATP and JC-1 were applied to assess mitochondrial function. Western blotting and immunofluorescence were utilized to elucidate the regulatory effect of DDB on Wnt5a/p-CaMKII pathway and mitochondrial fission. Molecular docking, PoseView and cellular thermal shift assay were employed to further validate the molecular mechanism of DDB binding to Wnt5a. Results DDB administration significantly inhibited body/liver weight gain and hepatic fat accumulation in NAFLD mice, reducing TG and TC levels in serum, and improving mitochondrial function. RNA-sequencing highlighted energy metabo