Non-alcoholic fatty liver disease (NAFLD) is a potentially serious disease that affects 30 % of the global population and poses a significant risk to human health. However, to date, no safe, effective and appropriate treatment modalities are available. In recent years, ferroptosis has emerged as a significant mode of cell death and has been found to play a key regulatory role in the development of NAFLD. In this study, we found that arbutin (ARB), a natural antioxidant derived from Arctostaphylos uva-ursi (L.), inhibits the onset of ferroptosis and ameliorates high-fat diet-induced NAFLD in vivo and in vitro. Using reverse docking, we identified the demethylase fat mass and obesity-related protein (FTO) as a potential target of ARB. Subsequent mechanistic studies revealed that ARB plays a role in controlling methylation of the SLC7A11 gene through inhibition of FTO. In addition, we demonstrated that SLC7A11 could alleviate the development of NAFLD in vivo and in vitro. Our findings identify the FTO/SLC7A11 axis as a potential therapeutic target for the treatment of NAFLD. Specifically, we show that ARB alleviates NAFLD by acting on the FTO/SLC7A11 pathway to inhibit ferroptosis.

非酒精性脂肪肝病 (NAFLD) 是一种潜在的严重疾病，影响全球 30% 的人口，对人类健康构成重大风险。然而，迄今为止，尚无安全、有效和适当的治疗方式。近年来，铁死亡已成为一种重要的细胞死亡模式，并被发现在 NAFLD 的发展中发挥着关键的调节作用。在这项研究中，我们发现熊果苷 (ARB) 是一种从Arctostaphylos uva-ursi (L.)中提取的天然抗氧化剂，在体内和体外均可抑制铁死亡的发生并改善高脂饮食诱导的 NAFLD。通过反向对接，我们确定去甲基酶脂肪量和肥胖相关蛋白（FTO）是 ARB 的潜在靶点。随后的机制研究表明，ARB 通过抑制 FTO 来控制SLC7A11基因的甲基化。此外，我们证明SLC7A11可以在体内和体外缓解NAFLD的发展。我们的研究结果确定 FTO/SLC7A11 轴是治疗 NAFLD 的潜在治疗靶点。具体来说，我们表明 ARB 通过作用于 FTO/SLC7A11 通路抑制铁死亡来缓解 NAFLD。