Bisphenols exposure and non-alcoholic fatty liver disease: from environmental trigger to molecular pathogenesis.

Bisphenols (BPs), including bisphenol A (BPA) and its substitutes (BPS, BPF), are ubiquitous environmental contaminants with emerging links to metabolic disorders. This review synthesizes current evidence on the role of BP exposure in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), a global health crisis affecting 25% of adults worldwide. Epidemiological studies reveal significant positive associations between urinary/serum BP levels and NAFLD risk, particularly in males, with maternal exposure correlating to transgenerational metabolic dysfunction. Mechanistically, BPs disrupt hepatic lipid homeostasis by activating PPAR-γ and suppressing fatty acid oxidation while concurrently inducing insulin resistance via impaired IRS-1/PI3K/Akt signaling. Oxidative stress, NLRP3 inflammasome activation, and gut-liver axis perturbations further exacerbate steatosis and inflammation. Co-exposure with phthalates or high-fat diets amplifies hepatotoxicity, highlighting synergistic environmental risks. Critically, developmental and sex-specific susceptibility underscores the need for tailored interventions. We propose preventive strategies to mitigate NAFLD progression, including BP avoidance and policy reforms. This work bridges gaps between environmental epidemiology and molecular toxicology, emphasizing BPs as modifiable drivers of metabolic liver disease.