PFASs refer to a group of emerging pollutants that have garnered remarkable attention. Since PFASs were synthesized in the 1950s, they have become highly important chemical materials in industrial and consumer production [1]. They are widely used in the manufacturing of products designed to resist stains, oils, and water, such as non-stick cookware, stain-resistant textiles, food packaging, and even personal care products. PFASs are persistent organic pollutants that exhibit the characteristics of endocrine disruptors [2,3]. Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are representative substances of PFASs and are known for their persistent, bioaccumulative properties, and long-range transport [4]. PFOS can be absorbed by the human body through multiple pathways, with the consumption of contaminated water and food recognized as the main sources of non-occupational PFAS exposure in humans [5,6]. Although global regulations have imposed strict limits on their usage, the presence of PFASs in the body remains increased in some developing countries [7,8]. Therefore, the research in this field is meaningful.

Exposure to environmental pollutants has become a remarkable factor in non-alcoholic fatty liver disease (NAFLD), and experimental research has shown that exposure to PFAS can alter metabolic changes, causing fatty liver [9]. Nevertheless, the mechanisms behind PFAS-induced hepatic steatosis remain unclear. At present, PFOA functions as an agonist for peroxisome proliferator-activated receptor alpha (PPARα) [10]. Studies that involve primates and mice with PPARα gene knockouts, exposed to PFOA, have indicated that hepatic steatosis is induced by signaling pathways other than PPARα [11,12]. Kim et al. used systematic toxicological methods to show that PFOS may reduce SIRT1 expression, which was the molecular initiation event (MIE) that ultimately led to hepatic steatosis, and PPAR signaling was not considered in this study [13]. Findings from a proteomic study conducted on the human liver cell line HepG2 exposed to PFOA reveal that PFOA predominantly influences hepatic nuclear factor 4 alpha (HNF4A) and its associated protein (HNF1A). The same result also appeared in mice [14]. These studies indicated that PFOA can inhibit HNF4A. HNF4A is a member of the nuclear receptor family, primarily expressed in the liver, and serves as a central regulatory factor in lipid and glucose metabolism, cell differentiation, and development [15]. HNF4a gene abnormalities are closely associated with maturity-onset diabetes of the young, type 1, lipid metabolism, and liver health, including liver fat accumulation and high-density lipoprotein functionality issues [[16], [17], [18]]. Furthermore, another study conducted on human liver cells has found that PFOA can inhibit the function of HNF4A [19]. Epidemiological data also indicate the remarkable role of PFAS exposure in the progression of NAFLD [[20], [21], [22]].

Currently, molecular docking and molecular dynamics (MD) have the potential to be applied for identifying potential targets in the adverse outcome pathway (AOP) framework [[23], [24], [25]]. They offer distinct advantages in investigating the interaction between environmental pollutants and biomolecular receptors at the molecular level, thereby unveiling potential mechanisms underlying the toxicity of pollutants [26,27]. Therefore, this work employed molecular docking and MD to investigate the interaction mechanisms between PFASs and HNF4A and explore whether HNF4A possesses the capability to stably bind to PFASs. Additionally, the AOP triggered by PFASs, with HNF4A as the initiating molecule, was analyzed based on the transcriptomic data from the GEO database.