Non-alcoholic fatty liver disease (NAFLD), which is marked by the atypical buildup of lipids in the liver, ranks among the common chronic liver conditions [1]. It is closely linked to insulin resistance and genetic susceptibility and is an acquired liver injury induced by metabolic stress [2]. NAFLD is divided into two categories: simple steatosis (non-alcoholic fatty liver) and non-alcoholic steatohepatitis (NASH) [3]. Globally, approximately 32% of adults have NAFLD, with males (40%) having a higher prevalence than females (26%). The global prevalence of NAFLD has increased, from 26% in 2005 to 38% in 2016 and later studies [4]. NAFLD may advance to liver cirrhosis and hepatocellular carcinoma (HCC), potentially having a significant impact on the physical and mental well-being of patients, as well as their lifestyle [5]. Therefore, comprehending the exact mechanisms driving the onset of NAFLD is crucial for formulating effective therapeutic interventions.

The pathogenesis of NAFLD is linked to factors including abnormalities in lipid metabolism and oxidative reactions [6]. Ferroptosis is a type of cell death that is non-apoptotic and dependent on iron, characterized by the interplay between the cellular mechanisms that promote ferroptosis and those that provide defense against it [7]. When the activities within cells that encourage ferroptosis exceed the protective antioxidant capacity offered by the ferroptosis defense system, lipid peroxides build up in the cell membrane, resulting in cell death [8]. Lipid peroxidation during ferroptosis can induce hepatic simple steatosis and elicit inflammatory responses, thereby facilitating the development and advancement of NAFLD [9]. Therefore, modulating the interaction between ferroptosis death execution and defense systems in the liver is an effective strategy for preventing and treating NAFLD. However, there are currently no approved drugs for treating NAFLD. Consequently, the search for safe and effective drugs to treat NAFLD and its complications has become an urgent task.

A successful therapeutic approach for NAFLD involves the inhibition of oxidative stress and lipid peroxidation [10]. Research indicates that the primary trigger for ferroptosis is the excessive buildup of lipid peroxides, which arises from the conflict between the execution and defense mechanisms of ferroptosis [11]. The ferroptosis defense mechanism includes the SLC7A11-GSH-GPX4 axis and the FSP1-CoQ10 system [12]. The FSP1-CoQ10 pathway functions is a separate parallel mechanism, working alongside GPX4 and GSH to prevent phospholipid peroxidation and ferroptosis [13]. FSP1, located on the membrane, acts as a NAD(P)H-dependent oxidoreductase capable of reducing ubiquinone to ubiquinol. CoQ10 inhibits lipid peroxidation and ferroptosis by neutralizing lipid peroxide radicals [14]. Research conducted on liver-specific FSP1 knockout mice indicates that lacking FSP1 intensifies lipid buildup in the liver [15]. FSP1 activation exerts antioxidant effects by generating CoQ10 to inhibit cellular ferroptosis [16]. Research has found that vitamin E can protect CoQ10 from oxidative damage, aiding cells in enhancing their antioxidant capacity [17]. The system responsible for executing ferroptosis includes the production of PUFA-PL, the pathway of peroxidation, and the metabolism of iron [18]. The synthesis of PUFA-PL facilitated by LPCAT3 and ACSL4, and the peroxidation of PUFA-PL driven by ALOXs, is essential for ferroptosis [19]. Studies have shown that knocking out ACSL4 in mouse liver cells reduces hepatic lipid accumulation by lowering fatty acid oxidation [20]. Vitamin E can inhibit ACSL4 expression, improving ovarian dysfunction caused by ferroptosis [21]. Furthermore, recent research indicates that the ferroptosis inhibitor vitamin E can alleviate liver damage induced by HFD in mice by reducing lipid peroxidation. This implies that decreasing lipid peroxidation could represent a new and promising therapeutic target for NAFLD [22]. However, vitamin E has many side effects, such as potentially increasing the incidence of hemorrhagic stroke and prostate cancer [23].

Diosgenin is a type of natural steroidal glycoside primarily extracted from plants such as Leguminosae, Dioscoreaceae, Liliaceae, and Solanaceae [24]. Research has demonstrated that DG exhibits pharmacological effects, including anti-inflammatory, antioxidant, anti-hyperlipidemia, anti-cardiovascular disease, and anti-tumor properties [25]. Previous experimental studies have demonstrated that DG can significantly improve lipid metabolism disorders and hepatic steatosis; however, the precise mechanism by which it treats NAFLD remains unclear [26]. The onset and progression of NAFLD are significantly influenced by oxidative stress and lipid peroxidation during ferroptosis [27]. Therefore, our study aims to reveal whether DG can beneficially impact hepatic lipid metabolism and oxidative stress by modulating ferroptosis execution and defense systems in the liver 窗体顶端.