IRP2 contributes to COPD-associated hypoxic epithelial injury through regulation of Sestrin2-related stress responses and ferroptosis.

Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by persistent oxidative stress and airway epithelial injury. However, the molecular mechanisms linking iron metabolism and cellular stress responses in COPD remain unclear. This study aimed to investigate the role of iron regulatory protein 2 (IRP2) in COPD-associated epithelial injury. 16HBE and A549 cells were exposed to cigarette smoke extract (CSE) under a COPD-associated hypoxic microenvironment. IRP2 was silenced using shRNA, and Sestrin2 restoration experiments were performed. Cellular injury was evaluated by cell viability, ROS production, inflammatory cytokines, intracellular Fe²⁺ accumulation, ferroptosis-related proteins, and NRF2 activation. CSE exposure under a COPD-associated hypoxic microenvironment induced epithelial injury, accompanied by increased oxidative stress, inflammation, iron accumulation, and ferroptosis-related changes. IRP2 silencing alleviated these alterations and enhanced NRF2 nuclear activation with increased expression of antioxidant proteins. Restoration of Sestrin2 partially reversed the protective effects induced by IRP2 depletion. Furthermore, pharmacological inhibition of ferroptosis attenuated epithelial injury. IRP2 contributes to COPD-associated epithelial injury by regulating oxidative stress, iron homeostasis, and ferroptosis-related responses, providing new insights into the molecular mechanisms underlying COPD progression.

Supplementary information: The online version contains supplementary material available at https://doi.org/10.1007/s10616-026-01066-9.