CDKN2A alterations as possible molecular link between environmental pollutants and pathogenesis of liver cancer: Epidemiology, mechanisms, and insights.

Hepatocellular carcinoma (HCC) represents a global public health burden of increasing magnitude, driven by risk factors including viral hepatitis, metabolic dysfunction-associated fatty liver disease and various environmental carcinogens, which may inactivate key tumor suppressor genes or activates oncogenes. Recent studies have linked various environmental exposures with inactivation of tumor suppressor gene CDKN2A (cyclin dependent kinase inhibitor 2A) and its encoded proteins p16INK4a and p14ARF to various molecular pathways leading to hepatocarcinogenesis. Current studies suggest p16INK4a deficiency leads to the increase of reactive oxygen species (ROS) via p38/MAPK signaling mediating an inflammatory response signal. Chronic liver injury caused by metabolic stress, viral infections and environmental toxins like particulate matter, arsenic and aflatoxin B1 can inactivate CDKN2A by epigenetic silencing such as promoter hypermethylation. This inactivation disrupts cell cycle regulation, increases oxidative stress, and induces inflammation and fibrosis, hastening the progression of liver diseases into malignancy. CDKN2A methylation carries both clinical and public health ramifications, serving as potential biomarkers for early detection, prognostic evaluation and risk stratification. As such, reducing exposure to environmental carcinogens and enforcing strict air quality standards are considered effective public health strategies in preventing HCC. In this review, we summarized the role of CDKN2A in the pathogenesis of liver cancer in response to environmental carcinogens, discussed possible underlying molecular mechanisms and provided insights on possible effective strategies for the control of environmental carcinogen-driven liver cancer.