The regulation of oxidative stress response by epigenetic modifications in acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS), a life-threatening condition driven by diffuse alveolar-capillary injury and loss of redox homeostasis, still lacks effective targeted pharmacotherapies. Current management remains predominantly supportive, with lung-protective ventilation as the cornerstone of respiratory care. Although ARDS arises from diverse clinical insults, oxidative stress emerges as a shared pathogenic pathway across etiologies. Excessive reactive oxygen species (ROS) production not only directly injures epithelial and endothelial cells but also perpetuates inflammatory signaling. ROS generation and clearance are compartmentalized, governed by interconnected pathways that span multiple organelles and cellular processes, forming a dynamic redox network that becomes especially vulnerable during critical illness. Growing evidence implicates epigenetic mechanisms as key modulators of this redox-inflammation interface. In this review, we delineate how three pivotal epigenetic processes regulate oxidative stress in ARDS: DNA methylation, histone modifications, and non-coding RNAs. We also examine the crosstalk among these mechanisms and evaluate emerging interventions targeting these pathways, emphasizing both their therapeutic potential and the persistent challenges in clinical translation. Importantly, rather than viewing these mechanisms independently, this review integrates current evidence to highlight epigenetic regulation as a critical layer linking oxidative stress, inflammatory signaling, and cellular injury in ARDS. We further propose that effective therapeutic strategies may require stage-specific and cell-type-oriented modulation of epigenetic targets, rather than uniform systemic inhibition. By synthesizing these insights, this review aims to provide a conceptual framework that may help guide the development of more precise redox-targeted epigenetic interventions in ARDS.