Alpinetin Protects Against High‐Fat Diet‐Induced Hepatic Injury via Mitigating Oxidative Stress, and Ferroptosis Through Modulating LXRα

Nonalcoholic fatty liver disease (NAFLD) demonstrates an increasing incidence alongside metabolic syndromes. The present study aimed to investigate the effects and underlying mechanisms of alpinetin on hepatic injury using both in vivo and in vitro models. Mice were subjected to a high‐fat diet (HFD) and subsequently treated with either high‐ or low‐dose alpinetin. In vitro experiments employed palmitic acid (PA, 1 mM) to induce lipid deposition in mouse primary hepatocytes, which were then treated with varying doses of alpinetin. We observed that alpinetin mitigated HFD‐induced liver damage in a dose‐dependent manner by regulating triglycerides (TG), total cholesterol (TC), alanine aminotransferase (ALT), aspartate aminotransferase (AST), high‐density lipoprotein (HDL), and low‐density lipoprotein (LDL) levels, along with pathological alterations in liver tissues. Furthermore, alpinetin counteracted the HFD‐induced upregulation of lipid synthesis‐related genes (acetyl CoA carboxylase 1 [ Acc1 ], sterol regulatory element‐binding protein 1c [ Srebp1c ], stearoyl‐CoA desaturase‐1 [ Scd1 ]) and lipid accumulation in liver tissues. HFD‐feeding also induced oxidative stress and ferroptosis in mice, which were significantly reduced by alpinetin administration in a dose‐dependent fashion. Similarly, alpinetin markedly reduced PA‐induced apoptosis, lipid accumulation, mitochondrial dysfunction, oxidative stress, and ferroptosis in a dose‐dependent manner. Mechanistically, alpinetin reversed the downregulation of liver X receptor alpha (LXRα) induced by HFD or PA in mouse liver tissues and hepatocytes. Overexpressing LXRα was found to protect mouse hepatocytes from PA‐induced damage. Rescue assays demonstrated that LXRα deficiency negated the protective effects of alpinetin against PA‐induced hepatocyte injury. In conclusion, alpinetin ameliorates hepatic injury induced by an HFD in mice and PA‐induced damage in mouse hepatocytes by modulating LXRα.