The potential mechanism investigation of Lipocalin-2 in ferroptosis via the AMPK/SIRT3/FOXO3a axis in sepsis-associated acute kidney injury.
Sepsis-associated acute kidney injury (SA-AKI) is a common and severe complication of sepsis. Lipocalin-2 (LCN2), a biomarker for SA-AKI, has an undefined role and underlying molecular mechanism in regulating renal ferroptosis. This study aimed to elucidate the regulatory function and potential mechanism of LCN2 in renal ferroptosis during SA-AKI. In vivo, a murine sepsis model was established using cecal ligation and puncture (CLP), while in vitro, human renal tubular epithelial cells (HK-2) were stimulated with lipopolysaccharide (LPS) to mimic SA-AKI. Histopathological, biochemical, and molecular analyses were performed to assess renal injury, oxidative stress, inflammatory responses, and ferroptosis-related indicators. In vivo, LCN2 knockout significantly attenuated renal pathological damage, reduced oxidative stress and inflammatory cytokine expression, and inhibited renal ferroptosis. Mechanistically, LCN2 knockout enhanced AMPK phosphorylation and upregulated SIRT3 expression, promoted deacetylation of FOXO3a, and upregulated the expression of antioxidant and anti-ferroptotic proteins. In vitro, LCN2 overexpression exacerbated LPS-induced ferroptosis in HK-2 cells, whereas activation of AMPK or overexpression of SIRT3 reversed this effect, as reflected by improved markers of ferroptosis and oxidative stress. Collectively, our findings suggest that LCN2 may promote renal ferroptosis and contribute to the progression of SA-AKI, potentially involving inhibition of the AMPK/SIRT3/FOXO3a pathway. These observations indicate that LCN2 could be further explored as a candidate molecular target for the clinical treatment of SA-AKI.