Hypoxic Mesenchymal Stem Cell Exosome‐Derived SLC25A3 Ameliorates Bronchopulmonary Dysplasia by Modulating Macrophage Polarization and Oxidative Stress

ABSTRACT Bronchopulmonary dysplasia (BPD) is a prevalent chronic lung disease in preterm infants, characterized by dysregulated macrophage polarization and oxidative stress. While mesenchymal stem cell‐derived exosomes (MSC‐Exos) have shown protective effects against BPD, the role of exosomes derived from hypoxia‐preconditioned MSCs (Hypo‐Exos) remains unclear. This study aimed to investigate whether Hypo‐Exos alleviate BPD by modulating alveolar macrophage (AM) polarization and oxidative stress via the mitochondrial transporter SLC25A3. We utilized in vitro models of LPS‐induced M1 polarization and H 2 O 2 ‐induced oxidative stress in AMs, as well as an in vivo rat model of BPD induced by intermittent hypoxia. Our data demonstrate that hypoxic preconditioning enhanced exosome secretion from MSCs. Furthermore, hypoxic preconditioning promoted the packaging of SLC25A3 into these exosomes. Hypo‐Exos significantly suppressed M1 polarization, reduced oxidative stress, and ameliorated lung injury and dysfunction in BPD rats. Silencing SLC25A3 in MSCs abolished these protective effects. Mechanistically, SLC25A3 interacted with PTEN, leading to inhibition of PTEN expression and activation of the PI3K/AKT signaling pathway. Overexpression of PTEN reversed the beneficial effects of SLC25A3 on macrophage polarization and oxidative stress. These findings reveal that Hypo‐Exos deliver SLC25A3 to AMs, thereby downregulating PTEN, activating PI3K/AKT signaling, promoting M2 polarization, attenuating oxidative damage, and ultimately mitigating BPD progression. This study provides important mechanistic insights and suggests potential therapeutic avenues for exosome‐based treatment of BPD.