Pyk۲ 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 Pyk۲ inhibitor on sepsis in a mouse model. In this study, we investigated the regulatory role of Pyk۲ inhibitor in ferroptosis and sepsis-associated acute lung injury (ALI).Materials and Methods: A Pyk۲ 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, Pyk۲ expression was determined in serum samples of patients with sepsis. Further, the association between serum Pyk۲ levels and clinical features was determined.Results: Experimental mouse models revealed that treatment with Pyk۲ inhibitor TAE۲۲۶ 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 TAE۲۲۶ function, indicating that Pyk۲ promotes inflammation via ferroptosis induction. Analysis of clinical samples revealed that the serum Pyk۲ levels were significantly increased in patients with sepsis. The serum Pyk۲ levels were associated with APACHE۲ scores and ۳۰-day mortality. Further, we found a negative correlation between serum Pyk۲ and Fe۳+ levels, which was consistent with the mechanism identified in the mouse model.Conclusion: Pyk۲ inhibitor of ferroptosis is a promising therapeutic candidate against sepsis-related ALI.