M2 Macrophage-Derived Exosomes Ameliorate BPD by Inhibiting Ferroptosis via Suppression of the ZAKα-p38 Signaling Pathway

Objective: To explore the protective effect of M2-Exo on hyperoxia or inflammation-induced BPD models and clarify its antioxidant mechanism.

Method

In vitro AT cell injury models and in vivo BPD models were constructed by hyperoxia or LPS induction. M2-Exo were isolated, identified, and used to intervene in models. Oxidative stress and ferroptosis-related indicators (ROS, MDA, iron accumulation, GPX4), AT cell functional markers (AQP5, SPC), and ZAKα-p38 pathway activation contents were de-tected.

ZAKα overexpression was used to verify pathway dependence. Results: M2-Exo intervention significantly enhanced AT cell viability, upregulated the expression of AQP5 and SPC, and reversed alveolar simplification. Concurrently, it effectively sup-pressed hyperoxia or LPS-induced oxidative stress and ferroptosis, as evidenced by re-duced contents of ROS and MDA, diminished iron accumulation, and GPX4 expression.

Mechanistically, M2-Exo significantly inhibited the activation of the ZAKα-p38 pathway, and ZAKα overexpression could antagonize the antioxidant, anti-ferroptotic, and AT cell protective effects of M2-Exo. Conclusions: M2-Exo alleviate AT cell oxidative stress and ferroptosis by inhibiting the ZAKα-p38 pathway, thereby improving hyperoxia or in-flammation-induced BPD and providing a new strategy and molecular target for the antioxidant treatment of BPD.