The ferroptosis inhibitor NUPR1 coordinates the mitochondrial response to oxidative stress and cell metabolism during COPD pathogenesis in the lung.

Chronic obstructive pulmonary disease (COPD) is characterized by chronic injury and oxidative stress leading to progressive lung tissue destruction. Emerging evidence suggests that regulated cell death pathways, particularly ferroptosis, contribute to COPD pathology. We previously identified decreased expression of the stress response protein and known ferroptosis inhibitor nuclear protein 1 (NUPR1) in alveolar type 2 cells from COPD patients. Here, we demonstrate that NUPR1 inhibition exacerbates iron accumulation, enhances lipid peroxidation, impairs mitochondrial function, disrupts cellular metabolism, and increases oxidative stress in lung epithelial cells. Furthermore, Nupr1-/- mice exhibit mitochondrial abnormalities, increased oxidative damage, and lung tissue changes consistent with emphysema. Collectively, our findings establish NUPR1 as a critical regulator of ferroptosis, stress responses, mitochondrial integrity, as well as metabolic balance in the lung and suggest reduced NUPR1 contributes to COPD pathogenesis.