Melatonin inhibits ferroptosis by activating CREB-GPX4/ferritin axis in cigarette smoke-induced chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a global public-health concern due to its currently high morbidity and mortality. Cigarette smoke (CS) exposure, the primary inducer of COPD, can provoke ferroptosis in lung epithelial cells. Melatonin, a neurohormone, has potential anti-inflammatory and anti-oxidative capacities. In this study, we investigated the protective effects of melatonin on CS exposure-induced COPD mice, and its underlying mechanisms of actions. The results showed that CS exposure caused obvious lipid peroxidation and the accumulation of ferrous (Fe²⁺) with the decreased expression of melatonin receptor (MT), thus triggered ferroptosis of lung epithelial cells in vitro and in vivo. In vitro, melatonin upregulated xCT, GPX4 and ferritin (FTH1/FTL) expression, reversed the CSE-induced ferroptosis depending on activated MT with the elevated phosphorylation of cAMP response element-binding protein (CREB^ser133). CREB knockdown (KD) caused melatonin failure to upregulate GPX4 and FTH1/FTL expression, thus did not inhibit CSE-induced ferroptosis of airway epithelial cells. Moreover, after suppressing the transcriptional regulation of p-CREB, melatonin again failed to promote GPX4 and FTH1/FTL expression and inhibit CSE-induced ferroptosis. The mechanistic dissection showed that melatonin led to the nuclear translocation of p-CREB which in turn bound to the promoter regions of GPX4 and FTH1/FTL genes, promoted their expression. In CS-induced COPD mice, melatonin alleviated pulmonary inflammation, emphysema and airway remodeling, improved lung function via activating the CREB-GPX4/ferritin signaling axis and inhibiting ferroptosis of pulmonary epithelial cells. Taken together, our findings indicates that melatonin inhibits CS-induced ferroptosis via activating CREB-GPX4/ferritin axis depending on activated MT. These findings can help lead to promising protective strategies for COPD.