LCN2 depletion aggravates sepsis-induced liver injury by regulating PTGS2-dependent ferroptosis

<b>Background:</b> Sepsis-induced liver injury (SILI) is an independent risk factor for organ dysfunction and mortality in critical care units. <b>Methods:</b> In this study, the roles of lipocalin 2 (LCN2) in SILI were investigated because LCN2 expression was increased in liver tissues of the septic mice induced by caecal ligation and puncture (CLP), as well as in hepatocytes treated with lipopolysaccharide (LPS). To evaluate liver injury in mice, the levels of alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) were measured in both serum and liver tissues. Oxidative stress was evaluated by measuring the levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) in serum and liver samples. Additionally, ferroptosis was assessed by examining the expression of prostaglandin endoperoxide synthase 2 (PTGS2), solute carrier family 7 member 11 (SLC7A11), and glutathione peroxidase 4 (GPX4) in liver tissue. <b>Results:</b> The results demonstrated that LCN2 depletion significantly exacerbated SILI, oxidative stress, and ferroptosis. Moreover, in <i>in vitro</i> sepsis model, LCN2 overexpression notably ameliorated LPS-induced cell injury, oxidative stress, and ferroptosis by inhibiting PTGS2 expression. <b>Conclusion:</b> In conclusion, our study provides evidence that LCN2 depletion aggravates SILI by regulating PTGS2-mediated ferroptosis.