Bronchopulmonary dysplasia (BPD) is a chronic lung disease that commonly occurs in preterm infants, often necessitating mechanical ventilation and oxygen therapy (Gilfillan M et al., 2021). It is characterized by arrested alveolar development, decreased alveolar count, enlarged alveolar cavities, simplified alveolar structure, and impaired pulmonary vascular function, ultimately compromising pulmonary function (Maria Jesús del Cerro et al., 2014). Survivors of BPD often experience chronic wheezing, frequent respiratory infections and exercise intolerance during adulthood (Caskey S et al., 2016). Despite the challenges faced by patients with BPD, only a limited number of drugs are currently available owing to inconsistent efficacy or adverse effects (Ryan et al., 2023). Therefore, effective therapies and approaches to prevent or reduce BPD and long-term respiratory morbidity remain urgently needed.

Abnormal inflammatory responses and oxidative stress are the primary etiological factors of BPD. Elevated levels of oxidative stress markers, such as lipid peroxide and malondialdehyde (MDA), have been detected in the plasma and bronchoalveolar lavage fluid of premature infants with BPD(Fabiano et al., 2016). Therefore, exploring antioxidant strategies for preventing and treating this condition is warranted. However, administering antioxidants (i.e., vitamins and micronutrients) to alleviate superoxide levels is insufficient to completely rescue BPD(Ferrante et al., 2022; Folz et al., 1999; Kiskurno et al., 2020; Paturi et al., 2021). This necessitates novel therapeutic agents to effectively treat BPD.

Nuclear factor erythroid 2-like 2 (NFE2L2), also known as Nrf2, coordinates the transcriptional activation of genes crucial for cellular protection, anti-inflammatory responses, tissue regeneration, and host defense in response to various oxidative stimuli, including hyperoxia (Cho et al., 2002a, 2002b). Nrf2 deficiency has been reported to exacerbate hyperoxia-induced endothelial dysfunction and abnormal angiogenesis in BPD(Amata et al., 2017; Chandra et al., 2020). The Nrf2 activator curcumin potentially mitigates hyperoxic lung injury (Sakurai et al., 2011; Sakurai, R. et al., 2013). Furthermore, sulforaphane, a well-recognized Nrf2 inducer, inhibits hyperoxia-induced lung inflammation in neonatal mice (McGrath-Morrow et al., 2014). We have previously reported that sodium propionate exerts protective effects against alveolar simplification and aberrant angiogenesis in BPD through an Nrf2-dependent mechanism (Chen et al., 2021). Therefore, modulation of the Nrf2 signaling pathway may represent a novel therapeutic approach for the treatment of BPD (Q. Liu et al., 2019).

MOTS-c is a mitochondrial peptide encoded by a small open reading frame within the mitochondrial 12S rRNA gene (Kim et al., 2018). Under stressful conditions, MOTS-c can rapidly translocate from the mitochondria to the nucleus and enhance the transcriptional activity of Nrf2(Kim et al., 2018; Xiao et al., 2023). In addition, low circulating MOTS-c levels in humans are associated with impaired coronary endothelial function (Qin et al., 2018). MOTS-c peptides effectively inhibit vascular calcification and myocardial remodeling (Wei et al., 2020). These findings suggested that MOTS-c can potentially improve vascular endothelial function. Therefore, we hypothesized that MOTS-c could inhibit oxidative stress by activating Nrf2 and provide beneficial effects by attenuating impaired pulmonary angiogenesis in BPD. To this end, we investigated the role of MOTS-c in hyperoxia-induced BPD and elucidated its underlying mechanism.