Soy isoflavones improve sympathetic nervous system-driven non-alcoholic fatty liver disease through estrogen-like effects

This study investigated the advantages of gerbils as a sympathetic nervous system (SNS)-driven model for non-alcoholic fatty liver disease (NAFLD) and evaluated the therapeutic potential of soy isoflavones (SIFs). Gerbils exhibited unique SNS characteristics, with an adrenal gland-to-kidney weight ratio 2–3 times higher than that of C57BL/6 mice and Wistar rats, demonstrating elevated levels of adrenaline (AE) and noradrenaline (NE) as well as more pronounced anxiety-like behaviors, indicating enhanced SNS activity. Additionally, gerbils possessed liver lipid metabolism and storage capacities similar to humans, along with a simple genetic background, allowing them to more accurately reflect the pathogenesis of NAFLD. This study employed ELISA, marble-burying tests, Oil Red O staining, H&E staining, laser speckle contrast imaging, TUNEL staining, immunofluorescence, and qRT-PCR to systematically evaluate the NAFLD model in gerbils and investigate the therapeutic effects and underlying mechanisms of SIFs on NAFLD. The study found that SIFs could reduce hepatic fat deposition, improve liver function, and downregulate the expression levels of cGAS and STING in the liver by modulating the ER–cGAS–STING pathway, thereby suppressing inflammatory responses. These findings confirmed the suitability of gerbils as an ideal model for studying SNS-induced NAFLD and revealed the potential therapeutic value of SIFs in ameliorating NAFLD through specific signaling pathways. This research provided important insights for a deeper understanding of NAFLD pathogenesis and the development of novel treatment strategies.