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<p>Non-alcoholic fatty liver disease is characterized by excessive lipid accumulation in the hepatocytes and is one of the main causes of cryptogenic cirrhosis. Bioactive compounds derived from natural products offer a safe and effective intervention. In this study, we isolated musizin from the aerial parts of <i>Rhamnus wightii</i> Wight &amp; Arn., Rhamnaceae, and synthesized three semisynthetic derivatives: musizin diacetate, musizin dimethylether, and musizin thiosemicarbazone from musizin. We then compared their physicochemical properties, docking, and ADMET profiles <i>in silico</i>. Molecular docking against the PPARα ligand binding domain (PDB: 1I7G) revealed that musizin thiosemicarbazone formed three major hydrogen bonds (MET220, GLU282, GLU286) with a binding energy of −6.83&#xa0;kcal/mol and an inhibition constant of 9.9&#xa0;µM, accompanied by superior ligand efficiency (0.41) over musizin and fenofibrate. ADMET predictions showed that musizin thiosemicarbazone obeys Lipinski’s rule of five, with optimal log P (2.32), improved aqueous solubility (c log S = −4.62), low mutagenicity, and a significant drug score (0.53) among all the molecules. <i>In vitro</i>, musizin thiosemicarbazone (50&#xa0;µM) significantly attenuated lipotoxicity and triacylglyceride-induced steatosis in palmitate-oleate-treated HepG2 cells by reducing intracellular lipid droplets by 64% (<i>p</i> &lt; 0.01) and restoring cell viability to 94% of control. The results suggest that a derivative of musizin thiosemicarbazone is a potent, orally bioavailable peroxisome proliferator-activated receptor alpha modulator with dual corrective effects on lipid homeostasis and hepatocellular safety, supporting its further development as a lead molecule for non-alcoholic fatty liver disease therapy.</p> Graphical Abstract <p></p>

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Musizin from Rhamnus wightii and Its Derivatives Attenuate Non-Alcoholic Fatty Liver Disease in Palmitate Oleate–Induced HepG2 Hepatocytes

  • 期刊论文

  • 发表日期：

    2026年1月22日

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  • Tharsius Raja William Raja,
  • Antony Stalin,
  • Veeramuthu Duraipandiyan,
  • Kedike Balakrishna,
  • Savarimuthu Ignacimuthu,
  • A. Jennifer Christy,
  • Michael Pillay

摘要

Non-alcoholic fatty liver disease is characterized by excessive lipid accumulation in the hepatocytes and is one of the main causes of cryptogenic cirrhosis. Bioactive compounds derived from natural products offer a safe and effective intervention. In this study, we isolated musizin from the aerial parts of Rhamnus wightii Wight & Arn., Rhamnaceae, and synthesized three semisynthetic derivatives: musizin diacetate, musizin dimethylether, and musizin thiosemicarbazone from musizin. We then compared their physicochemical properties, docking, and ADMET profiles in silico. Molecular docking against the PPARα ligand binding domain (PDB: 1I7G) revealed that musizin thiosemicarbazone formed three major hydrogen bonds (MET220, GLU282, GLU286) with a binding energy of −6.83 kcal/mol and an inhibition constant of 9.9 µM, accompanied by superior ligand efficiency (0.41) over musizin and fenofibrate. ADMET predictions showed that musizin thiosemicarbazone obeys Lipinski’s rule of five, with optimal log P (2.32), improved aqueous solubility (c log S = −4.62), low mutagenicity, and a significant drug score (0.53) among all the molecules. In vitro, musizin thiosemicarbazone (50 µM) significantly attenuated lipotoxicity and triacylglyceride-induced steatosis in palmitate-oleate-treated HepG2 cells by reducing intracellular lipid droplets by 64% (p < 0.01) and restoring cell viability to 94% of control. The results suggest that a derivative of musizin thiosemicarbazone is a potent, orally bioavailable peroxisome proliferator-activated receptor alpha modulator with dual corrective effects on lipid homeostasis and hepatocellular safety, supporting its further development as a lead molecule for non-alcoholic fatty liver disease therapy.

Graphical Abstract