Xenobiotic-induced liver injury: Molecular mechanisms and disease progression

Environmental xenobiotics comprising a wide array of natural and synthetic chemicals are an escalating global health concern due to their persistent presence in ecosystems and their profound impact on human liver health. The liver, as the body's principal detoxification organ, is especially vulnerable to these substances, which are commonly encountered through ingestion, inhalation, or dermal exposure. This review systematically categorizes key classes of environmental xenobiotics, including aflatoxins, alcohol, polychlorinated biphenyls (PCBs), per- and polyfluoroalkyl substances (PFAS), polycyclic aromatic hydrocarbons (PAHs), pesticides, heavy metals, bisphenol A (BPA), aristolochic acids, cyanotoxins, and nitrosamines, based on their sources and chemical properties. Drawing from both human and experimental studies, we examine a spectrum of hepatic outcomes ranging from steatosis, fibrosis, and cholestatic injury to hepatocellular carcinoma (HCC) and drug-induced liver injury (DILI). Evidence from recent cohort studies and in vivo models highlights that even low-dose, chronic exposures can lead to subtle yet progressive liver dysfunction, often modulated by host factors such as sex, age, diet, and pre-existing metabolic conditions. Mechanistically, xenobiotics exert hepatotoxic effects through pathways including cytochrome P450-mediated bioactivation, oxidative stress, mitochondrial impairment, DNA damage, inflammation, and immune dysregulation. We further explore how these chemicals disrupt critical signaling pathways involving nuclear receptors such as peroxisome proliferator-activated receptor alpha (PPARα), constitutive androstane receptor (CAR), and aryl hydrocarbon receptor (AhR), ultimately interfering with lipid homeostasis and bile acid metabolism. Additionally, the role of the gut-liver axis emerges as a crucial mediator, with alterations in gut microbiota composition influencing xenobiotic bioavailability and hepatic inflammation. Co-exposure scenarios, such as concurrent infections with hepatitis B or C viruses, appear to amplify liver injury, highlighting the complexity of environmental and biological interactions in liver disease pathogenesis. Taken together, this review underscores the urgent need for interdisciplinary research spanning toxicology, epidemiology, and systems biology to better understand the multifaceted effects of xenobiotics on liver health. These insights are critical to inform public health policies, refine risk assessment frameworks, and develop targeted interventions to mitigate liver-related morbidity and mortality associated with environmental exposures.