Abstract

There is a close correlation between intestinal barrier dysfunction and metabolic-associated fatty liver disease (MAFLD). Sennoside A (SA) is traditionally used for weight loss and laxation, and has been proven to exert beneficial effects on the regulation of glucose and lipid metabolism; however, its pharmacological activity in ameliorating MAFLD remains unclear. The present study was designed to address this research gap and achieve three core objectives: 1) Verify the therapeutic efficacy of SA on HFD-induced MAFLD in mice; 2) Clarify whether SA exerts protective effects on intestinal barrier structure and function during MAFLD improvement; 3) Explore the underlying molecular mechanisms involving inflammation and mitochondrial function regulation. To induce MAFLD, C57BL/6 mice recieved a high-fat diet (HFD) over a 16-week period, followed by 12 weeks of treatment with either a HFD supplemented with SA (30   mg/kg body weight) or a HFD alone; the control group received a normal diet throughout. After sacrifice, liver and intestinal tissues were harvested for subsequent analyses. Consistent with our hypothesis, SA significantly alleviated hepatic steatosis and corrected abnormal lipid metabolism, reduced metabolic inflammation, and preserved intestinal barrier structure and function in treated mice. Mechanistically, SA protects intestinal barrier function by modulating two key pathways: inhibiting TLR4/NF-κB-mediated inflammation and restoring mitochondrial quality control (MQC, including preserving mitochondrial membrane potential, suppressing mPTP opening, and regulating mitophagic flux and dynamics). This study provides direct experimental evidence that SA ameliorates MAFLD, possibly through a novel “intestinal barrier protection” mechanism, which links anti-inflammatory effects and mitochondrial function regulation. Biologically, this finding reveals a critical “intestinal-mitochondrial-liver” crosstalk in MAFLD progression; clinically, it highlights SA as a p