Particulate matter exposure induced COPD-like pathology in mice via excessive oxidative stress, ferroptosis, and mitochondrial dysfunction, which was ameliorated by inhibiting ACSL4 with deferoxamine.
Inhibition of ACSL4-mediated ferroptosis ameliorates particulate matter-induced COPD-like pathology, suggesting ACSL4 as a potential therapeutic target.
Abstract Rationale Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease characterized by chronic inflammation and is a leading cause of global mortality. Although tobacco smoking is the main risk factor for COPD, persistent exposure to particulate matter (PM) is also a major contributor to COPD. However, the mechanisms underlying PM’s impact on COPD progression remains unclear. The pathogenesis of COPD is thought to be associated with excessive oxidative stress resulting from disrupted iron homeostasis. Therefore, in this study, we investigate the association between PM and ferroptosis in the pathogenesis of COPD. Methods COPD-like pathology was induced in mice by exposure to PM, and lung tissues were collected for histological analysis. qPCR and immunofluorescence staining were performed to assess the expression of pro-inflammatory cytokines and markers of lung injury, including infiltration of inflammatory cells, and factors related to ferroptosis and mitochondrial dysfunction. In vitro, lung epithelial cells were treated with PM with or without deferoxamine (DFO), a ferroptosis inhibitor, followed by assessments of ROS levels, expression of pro-inflammatory cytokines and ferroptosis markers, and mitochondrial dysfunction. Results Mice exposed to particulate matter (PM) exhibited COPD-like lesions, including increased mucin production and alveolar airspace enlargement. Their lung tissues also showed characteristics of COPD, such as increased inflammatory cell infiltration, elevated MMP activity, an increased number of apoptotic cells, and elevated ROS levels. Moreover, PM upregulated the expression of factors associated with ferroptosis, which consequently induced mitochondrial dysfunction. PM strongly induced oxidative stress, leading to iron accumulation and lipid peroxidation. As a result, chronic inflammation was induced, driven by increased levels of inflammatory cytokines. Treatment with DFO inhibited the PM-induced expression of ACSL4, ALOX5, ALOX12, NCOA4, Slc1A5, and NOX4. Notably, ACSL4 was identified as the most effectively inhibited target among these factors. This reduction was confirmed to not only attenuate excessive iron accumulation and lipid peroxidation but also suppress the chronic inflammatory response. Conclusions These findings suggest that PM induces COPD-like pathology by causing excessive oxidative stress, which leads to ferroptosis and mitochondrial dysfunction. Furthermore, the results indicate that this PM-induced pathology can be ameliorated, particularly upon the inhibition of ACSL4. Therefore, we propose that ACSL4 may serve as a promising therapeutic target for PM-induced COPD. This abstract is funded by: This work was supported by Korea Basic Science Institute (National research Facilities and Equipment Center) grant funded by the Ministry of Science and ICT (No. RS-2024-00405028) and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. RS-2025-24533104).
Boo et al. (Fri,) conducted a other in Chronic obstructive pulmonary disease (COPD). Particulate matter (PM) exposure and deferoxamine (DFO) vs. Control (no PM or no DFO) was evaluated on COPD-like pathology, ferroptosis markers, and mitochondrial dysfunction. Particulate matter exposure induced COPD-like pathology in mice via excessive oxidative stress, ferroptosis, and mitochondrial dysfunction, which was ameliorated by inhibiting ACSL4 with deferoxamine.