Pyk2 regulates sepsis-induced lung injury via ferroptosis

OBJECTIVE(S): The onset of sepsis represents a hyper-inflammatory condition that can lead to organ failure and mortality. Recent findings suggest a potential beneficial effect of protein tyrosine kinase Pyk2 inhibitor on sepsis in a mouse model. In this study, we investigated the regulatory role of Pyk2 inhibitor in ferroptosis and sepsis-associated acute lung injury (ALI). MATERIALS AND METHODS: A Pyk2 inhibitor or a ferroptosis regulator were injected into mice sustaining sepsis-induced ALI and the effects on lung injury and pro-inflammatory response were evaluated. Clinically, Pyk2 expression was determined in serum samples of patients with sepsis. Further, the association between serum Pyk2 levels and clinical features was determined. RESULTS: Experimental mouse models revealed that treatment with Pyk2 inhibitor TAE226 can significantly alleviate lung injury, downregulate pro-inflammatory responses and decrease markers of ferroptosis, which were induced by LPS. Both upregulation and downregulation of ferroptosis can lead to the loss of TAE226 function, indicating that Pyk2 promotes inflammation via ferroptosis induction. Analysis of clinical samples revealed that the serum Pyk2 levels were significantly increased in patients with sepsis. The serum Pyk2 levels were associated with APACHE2 scores and 30-day mortality. Further, we found a negative correlation between serum Pyk2 and Fe(3+) levels, which was consistent with the mechanism identified in the mouse model. CONCLUSION: Pyk2 inhibitor of ferroptosis is a promising therapeutic candidate against sepsis-related ALI.