WWOX protects against ferroptosis to alleviate acute lung injury by mediating p53 deacetylation

Ferroptosis plays a crucial role in the pathophysiology of acute lung injury (ALI), but its regulatory mechanisms remain elusive. In this study, we found that WW domain-containing oxidoreductase (WWOX) acts as a pivotal regulator of lung epithelial cell ferroptosis during ALI. Initially, the involvement of ferroptosis in the onset and progression of lipopolysaccharide (LPS)-induced ALI was confirmed through ferrostatin-1 (Fer-1) intervention. RNA-seq revealed a negative correlation between WWOX expression and ferroptosis. Erastin consistently exacerbated LPS-induced ALI and ferroptosis, and these effects were significantly mitigated by WWOX overexpression. Mechanistically, SLC7A11 is negatively regulated by p53, a ferroptosis-related gene. In this study, we observed that WWOX mediated p53 deacetylation and enhanced SLC7A11 expression. Our findings suggest that WWOX is a crucial regulator of ferroptosis anda potential therapeutic target for ALI treatment.