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

## TL;DR

M2 macrophage-derived exosomes help treat a lung disease in premature infants by reducing cell damage through a specific signaling pathway.

## Contribution

The study reveals a novel mechanism by which M2 macrophage-derived exosomes inhibit ferroptosis via the ZAKα-p38 pathway in bronchopulmonary dysplasia.

## Key findings

- M2-Exo improved alveolar epithelial cell viability and reversed alveolar simplification in BPD models.
- M2-Exo suppressed oxidative stress and ferroptosis by reducing ROS, MDA, and iron accumulation.
- The protective effects of M2-Exo were mediated through inhibition of the ZAKα-p38 signaling pathway.

## Abstract

Background: Bronchopulmonary dysplasia (BPD) is a common lung disease in premature infants. Hyperoxia-induced oxidative stress and ferroptosis are key pathological mechanisms leading to alveolar epithelial (AT) cell injury and impaired alveolar development. M2 macrophage-derived exosomes (M2-Exo), as intercellular communication carriers, have potential protective effects in regulating oxidative stress-related diseases, but the molecular mechanism by which they exert effects by regulating ferroptosis in BPD remains unclear. 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 detected. 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 suppressed hyperoxia or LPS-induced oxidative stress and ferroptosis, as evidenced by reduced 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 inflammation-induced BPD and providing a new strategy and molecular target for the antioxidant treatment of BPD.