Di(2-ethylhexyl) phthalate is the most prevalent phthalic acid ester, acting as a plasticizer by noncovalently binding to polyolefin plastics to enhance their flexibility, transparency, and durability [1]. DEHP is the most widely used phthalate in everyday life, making up approximately 50% of the world's phthalate production, surpassing 2 million tons [2]. DEHP is persistently released into the environment (air, soil, water, food) and can enter biological systems through ingestion, inhalation, or dermal contact, exerting detrimental health effects [3]. It is important to note that DEHP can migrate from the surface of materials that come into contact with food into the food itself, potentially causing more harmful effects on human health [4]. Notably, the widespread use of plastic-containing face masks during the recent global coronavirus pandemic has raised concerns about exposure to plastic additives, particularly phthalate esters [5,6]. With the increasing pollution of DEHP, a prompt treatment strategy is essential to mitigate their adverse effects on human health.

Earlier research suggested that exposure to DEHP might promote benign prostatic hyperplasia [7], induce liver tumors [8], disrupt the epithelial barrier [9], etc. Among its various health effects, hepatotoxicity is of paramount importance, as the liver is the body's primary detoxification organ [10]. According to Yu et al. [11], DEHP has the potential to be toxic to the human liver and is closely related to abnormalities in liver function indicators. Chronic exposure to DEHP leads to its accumulation in the liver, causing toxicity [12] and potentially inducing liver tumors [13]. The mechanisms underlying DEHP-induced hepatotoxicity are multifactorial, involving oxidative stress, apoptosis, inflammation, mitophagy, ferroptosis, and the activation of signaling pathways, as well as alterations in gut microbiota and metabolomics via the gut-liver axis [[14], [15], [16], [17], [18]]. Research shows that exposure of the liver to DEHP interferes with cholesterol metabolism, boosts the generation of oxygen-free radicals, triggers fibrosis, and could advance liver cancer development [19,20]. While there is growing evidence that DEHP exposure is associated with hepatotoxicity, the exact mechanisms remain unclear, and the precise molecular mechanisms have yet to be fully elucidated.

Lycopene is a potent antioxidant from the carotenoid family and is abundant in red fruits and vegetables. Lyc exhibits diverse biological activities, including antioxidative [21], anti-inflammatory [22], and antiapoptotic [23] effects. It has shown promise in ameliorating various liver ailments, such as alcoholic liver disease, hepatocellular carcinoma, nonalcoholic fatty liver disease, and hepatic fibrosis, as well as injury from ischemia/reperfusion, radiation, and fulminant hepatic failure [24]. Furthermore, Lyc has demonstrated hepatoprotective effects against environmental toxins such as DEHP [25], atrazine [26], aflatoxins [27], 2,3,7,8-tetrachlorodibenzo-p-dioxin [28], and bisphenol A [29]. A previous study identified that Lyc ameliorates DEHP-induced liver lipid metabolism disorders by suppressing the HIF-1α-induced PPARα/PPARγ/FXR/LXR system [30]. Given that the liver is a target for both DEHP toxicity and Lyc's protective actions, a comprehensive understanding of Lyc's impact on the hepatic metabolome and transcriptome is needed.

Metabolomics provides a comprehensive analysis of small-molecule metabolites, while transcriptomics focuses on the complete set of RNA transcripts within a cell or tissue [31]. Integration of these multiomics technologies provides a holistic view of the complex molecular processes in both health and disease [32]. This study aimed to evaluate the protective effects of Lyc against DEHP-induced liver damage in mice and to investigate the underlying mechanisms using an integrated metabolomic and transcriptomic approach. Our findings offer novel insights into the pharmacological effects of Lyc, suggesting that it may be a promising natural compound for the prevention and treatment of DEHP-induced hepatotoxicity.