FGF2 alleviates LPS-induced acute lung injury by inhibiting ferritinophagy-mediated ferroptosis in AT2 cells via the Hippo-YAP signaling pathway.

Abstract

BACKGROUND: Ferroptosis of type II alveolar epithelial (AT2) cells plays a crucial role in the pathological progression of acute lung injury (ALI). Although fibroblast growth factor-2 (FGF2) has been shown to exert protective effects against ALI, the underlying mechanisms remain largely unexplored. METHODS: The present study investigated the relationship between ferroptosis and FGF2 in the pathogenesis of ALI. RESULTS: Our study found that FGF2 administration mitigated lung pathology, respiratory dysfunction, inflammation, and oxidative stress induced by lipopolysaccharide (LPS). Conversely, genetic knockout of FGF2 exacerbated lung injury, inflammation, oxidative stress, and ferroptosis. RNA sequencing and bioinformatics analyses identified ferroptosis as a key target of FGF2-mediated protection. Pharmacological induction of ferroptosis negated the protective effects of FGF2 on AT2 cells. Mechanistically, co-immunoprecipitation assays revealed that FGF2 suppressed ferritinophagy-associated changes by disrupting the interaction between NCOA4 and FTH1. Further investigation revealed that FGF2 modulated this interaction via the Hippo-YAP signaling pathway. CONCLUSION: Collectively, these results underscored the therapeutic potential of targeting the FGF2-mediated suppression of ferritinophagy-induced ferroptosis in treating LPS-induced ALI.