Antioxidants in lung disease: Failures and pathways for success

Oxidative stress is widely invoked in the pathogenesis of lung disease, yet decades of antioxidant clinical trials have failed to produce meaningful therapeutic benefit. This persistent translational gap reflects not the invalidity of redox biology, but fundamental conceptual and design flaws in antioxidant drug development. Here, one argues that indiscriminate suppression of reactive oxygen species (ROS) ignores their essential physiological signaling roles, their strict spatiotemporal compartmentalization, and the heterogeneity of pathogenic ROS across lung diseases. This commentary proposes a precision redox medicine framework that integrates mechanistic specificity, biomarker-driven patient stratification, and targeted catalytic antioxidants. Recasting antioxidants as mechanism-based therapeutics rather than nonspecific scavengers may finally unlock their clinical potential.