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

Abstract

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 the stress response protein and known ferroptosis inhibitor nuclear protein 1 (NUPR1) as markedly downregulated in lung tissue 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 knockout mice exhibit mitochondrial abnormalities, increased oxidative damage, and lung tissue changes consistent with COPD pathology. Collectively, our findings establish NUPR1 as a critical regulator of ferroptosis, stress responses, mitochondrial integrity, and metabolic balance in the lung, highlighting its potential contribution to COPD pathogenesis.