JMJD3 deficiency alleviates lipopolysaccharide­induced acute lung injury by inhibiting alveolar epithelial ferroptosis in a Nrf2­dependent manner.

Acute respiratory distress syndrome (ARDS) is a deadly illness which presents with severe hypoxemia as well as diffuse alveolar damage. Jumonji domain­containing 3 (JMJD3), which belongs to the UTX/UTY JmjC­domain protein subfamily, is involved in infection, development, aging and immune disorders. However, the role of JMJD3 in acute lung injury (ALI) is still unclear. The present study explored the roles and potential mechanisms of JMJD3 in ALI. Alveolar epithelial cell­specific knockout of JMJD3 mice and A549 alveolar epithelial cells were used to investigate the function of JMJD3 in ALI. Lipopolysaccharide (LPS) was used to establish an in vivo and in vitro ALI model. The expression of JMJD3 in murine lung tissue and alveolar epithelial cells was detected. Pathological injury of lung tissue and alveolar epithelial cells was also investigated following inhibition of JMJD3. The results showed that JMJD3 expression was significantly increased in murine lung tissues and in A549 cells following LPS stimulation. JMJD3­deficient mice in alveolar epithelial cells exhibited alleviated lung pathological injury and ferroptosis following h stimulation. Mechanistically, it was found that JMJD3 knockout could increase the expression of nuclear factor erythroid­2­related factor­2 (Nrf2) in lung tissues challenged with h. However, Nrf2 overexpression by adenovirus could further enhance the anti­ferroptotic effect from JMJD3 silence in h­treated A549 cells. Taken together, the present study revealed that JMJD3 deficiency may relieve LPS­induced ALI by blocking alveolar epithelial ferroptosis in a Nrf2­dependent manner, which may serve as a novel therapeutic target against ALI.