Abstract
Air pollution is a leading global environmental health risk, responsible for millions of premature deaths worldwide each year. Although traditionally associated with respiratory and cardiovascular diseases, accumulating epidemiological and mechanistic evidence now demonstrates that air pollution acts as a systemic toxicant, contributing to a wide spectrum of pathologies across nearly all major organ systems. These include pulmonary and extrapulmonary malignancies, neurodegenerative disorders, cardiovascular and renal diseases, metabolic dysfunction-associated fatty liver disease, dermatological conditions, and sensory organ impairment. In this comprehensive review, we synthesize large-scale population studies, experimental models, and molecular evidence to define air pollution as a multi-organ pathogenic exposure driven by convergent biological mechanisms. Disease development across organs is driven by shared mechanisms such as oxidative stress, inflammation, epigenetic changes, and extracellular vesicle signaling, while organ-specific exposure pathways determine tissue vulnerability. Importantly, we emphasize that disease risk is not dictated by exposure alone. Genetic susceptibility plays a decisive role in shaping individual responses to air pollution, with polygenic risk scores and functional variants in detoxification, antioxidant, immune, and host-defense pathways modifying exposure-response relationships. Evidence from human cohorts and genetically defined animal models underscores gene-environment interactions as key drivers of interindividual heterogeneity in pollution-related disease. By integrating mechanistic convergence with organ-specific exposure biology and genetic susceptibility, this review reframes air pollution as a systemic driver of chronic disease. We further identify critical knowledge gaps related to real-world multipollutant exposure, biological resilience, and precision prevention, providing a conceptual foundation for targeted interventions and risk stratification in pollution-exposed populations.