In recent decades, the consumption of sugar-sweetened beverages and sweets has increased significantly, especially among children and adolescents [1]. A survey conducted in 11 European countries showed that 11-17% of children's energy intake comes from added sugars [2]. In the United States, added sugars intake accounted for 14.3% of total energy intake among teens [3]. The health effects of excessive sugar intake have gained global attention recently. In 2015, the World Health Organization recommended limiting free sugars to no more than 10% of total daily energy intake [4]. Since then, the consumption of sugars has gradually declined in some developed countries. However, the daily intake of sugars, particularly fructose, is still rising among people in low- and middle-income countries due to widespread urbanization and economic development, which increase the availability of sugar-sweetened beverages [5].

Fructose, a highly sweet monosaccharide, is the main component of sucrose (a disaccharide of glucose and fructose) and high-fructose corn syrup (55% fructose: 45% glucose), which are the two most commonly used sweeteners in the food industry [6]. An increasing number of epidemiological studies have linked fructose consumption to the development and progression of metabolic disorders, including obesity, non-alcoholic fatty liver disease (NAFLD), type 2 diabetes mellitus, and cardiovascular disease [1,5,7]. Despite the biochemical pathways of fructose in the body have been elucidated since the 1990s, the effects of fructose on metabolic diseases have only recently been studied.

NAFLD, more recently known as metabolic-associated fatty liver disease, is a prevalent chronic liver disease that is becoming a global health threat [8,9]. In 2022, it is estimated that the overall global prevalence of NAFLD is approximately 36-38% [9,10]. The initial stage of NAFLD is excessive hepatic lipid accumulation, and further deterioration leads to non-alcoholic steatohepatitis (NASH), characterized by hepatocyte damage and ballooning, hepatic inflammation, and fibrosis [1]. NAFLD is commonly associated with obesity, but it is increasingly found in non-obese individuals. Overall, approximately 40% of people with NAFLD worldwide are not obese, yet they have high mortality rates and share the same unhealthy metabolic profile as obese NAFLD patients [11,12]. Non-obese NAFLD patients may even have a worse prognosis and develop cirrhosis more rapidly than obese NAFLD patients [12].

More worryingly, adolescent NAFLD has become a growing health crisis worldwide. The prevalence of pediatric NAFLD in the United States reportedly doubled from the late 1980s to 2010 [13]. Previous studies showed that 34% of overweight or obese youths aged 1-19 years have NAFLD [14]. Currently, numerous epidemiological studies have demonstrated a positive correlation between fructose intake in adolescents and the incidence of NAFLD [6]. However, few studies addressed the relationship between high fructose intake and histopathological changes in NAFLD during childhood and adolescence and its underlying molecular mechanisms, even though children and adolescents are major consumers of fructose. Most recently, it has been reported that an 8-week dietary sugar restriction can reduce de novo lipogenesis and hepatic lipids in adolescent boys with NAFLD, suggesting that dietary sugar intake may play an important role in the development of NAFLD in childhood and adolescence [15]. In addition, further studies indicated that fructose has varying degrees of deleterious effects on rats of different ages [16,17]. It is shown that high-fructose corn syrup intake has a more profound effect on lipid metabolism in childhood and adolescent rats than in other ages through mechanisms related to epigenetic regulation [17]. Therefore, it is essential to fully understand the deleterious effects of fructose on the liver in adolescents and the underlying mechanisms.

Considering that excessive fructose intake may lead to calorie overload and the onset of obesity, which may confuse the metabolic effects of fructose with the deleterious effects induced by obesity. Therefore, in this study, we used fructose to replace isoenergetic corn starch to control energy intake consistently and eliminate the effects caused by energy excess, aiming to investigate the metabolic effects of fructose on the liver during adolescence and the possible mechanisms.