miR-21-5p attenuates hyperoxia-induced lung injury by modulating YAP1-dependent ferroptosis

Background: Hyperoxia-induced acute lung injury (HALI) is a frequent and clinically relevant complication of oxygen therapy in critically ill patients. Excessive oxygen exposure induces severe oxidative stress and alveolar epithelial cell (AEC) injury, yet the upstream regulatory mechanisms governing regulated cell death under hyperoxic conditions remain incompletely understood. Ferroptosis, an iron-dependent form of lipid peroxidation-driven cell death, has recently been implicated in HALI pathogenesis. Methods: were established to investigate the role of miR-21-5p in ferroptosis regulation. Gain- and loss-of-function approaches were combined with molecular, biochemical, and histological analyses to evaluate ferroptosis-related phenotypes. The regulatory interaction between miR-21-5p and Yes-associated protein 1 (YAP1) was examined using dual-luciferase reporter and RNA immunoprecipitation assays. Results: Hyperoxic exposure markedly induced ferroptosis-associated features in AECs and lung tissue, characterized by increased lipid peroxidation, iron accumulation, and impaired antioxidant capacity. miR-21-5p expression was significantly downregulated under hyperoxic conditions, whereas YAP1 expression was increased. miR-21-5p directly targeted YAP1 and negatively regulated its expression. Restoration of miR-21-5p attenuated hyperoxia-induced ferroptosis, reduced oxidative stress, and improved lung injury, while miR-21-5p deficiency exacerbated ferroptosis-related alterations and aggravated HALI. Mechanistically, modulation of the miR-21-5p/YAP1 axis was associated with coordinated changes in key ferroptosis-related molecules, including ACSL4, SLC7A11, and GPX4. Conclusion: These findings identify miR-21-5p as an important upstream regulator of ferroptosis in hyperoxia-induced lung injury through YAP1-dependent mechanisms. The miR-21-5p/YAP1 axis contributes to redox imbalance and ferroptotic susceptibility in HALI, highlighting a potential regulatory pathway relevant to hyperoxia-associated pulmonary injury.