Current Issue

Knockout of LCN2 attenuates lung injury and ferroptosis in septic mice likely through inhibiting the TLR4/NF-κB signaling pathway

WANG Yi-Ren^1,2, YU Meng-Jie^1,2, DU Ruo-Li^1,2, HE Yu-Ying^2,3, ZHANG Yi-Xin⁴, WANG Jia-Hui², YE Hong- Wei^1,2, GAO Qin^1,2,*

¹Department of Physiology, Bengbu Medical University, Bengbu 233030, China；²Key Laboratory of Basic and Clinical Cardiovascular Diseases, Bengbu Medical University, Bengbu 233030, China；³School of Life Sciences, Bengbu Medical University, Bengbu 233030, China；⁴School of Clinical Medicine, Bengbu Medical University, Bengbu 233030, China

Abstract

This study aimed to investigate the effects of lipocalin-2 (LCN2) gene knockout (LCN2KO) on cecal ligation and perforation (CLP) -induced lung injury and ferroptosis in septic mice, and further to clarify the potential role of the Toll-like receptor 4 (TLR4)/nuclear factor κB (NF-κB) pathway. A CLP model was established using LCN2KO mice. The levels of serum interleukin-6 (IL- 6) and IL-1β were measured by ELISA. The contents of malondialdehyde (MDA) and glutathione (GSH) in lung tissue were determined using the corresponding assay kits. Reactive oxygen species (ROS) levels in lung tissue were detected using dihydroethidium (DHE) fluorescent probe. The expression levels of ferroptosis-related proteins in lung tissue were assessed by Western blot. The results showed that, compared to wild-type (WT)-Sham group, WT-CLP group exhibited significant lung tissue damage, elevated serum IL-6 and IL-1β levels, increased MDA content and ROS level, decreased GSH content, up-regulated protein expression levels of LCN2 and TLR4, increased p-P65/P65 ratio, and significantly down-regulated protein expression levels of ferroptosis suppressor protein 1 (FSP1) and glutathione peroxidase 4 (GPX4). LCN2KO reversed these changes induced by CLP. Both TLR4 inhibitor TAK- 242 and NF-κB inhibitor PDTC down-regulated lung LCN2 protein expression, reversed sepsis-induced ferroptosis and lung injury, which is similar to the role of LCN2KO. These results suggest that LCN2KO may ameliorate lung injury in sepsis-induced mouse model by attenuating ferroptosis through modulating the TLR4/NF-κB signaling pathway.

Key words: lipocalin-2; sepsis-induced lung injury; ferroptosis; TLR4/NF-κB signaling pathway; inflammation

Received: 　　Accepted:

Corresponding author: 高琴　　E-mail:

DOI: 10.13294/j.aps.2025.0070

Citing This Article：

WANG Yi-Ren, YU Meng-Jie, DU Ruo-Li, HE Yu-Ying, ZHANG Yi-Xin, WANG Jia-Hui, YE Hong- Wei, GAO Qin. Knockout of LCN2 attenuates lung injury and ferroptosis in septic mice likely through inhibiting the TLR4/NF-κB signaling pathway. Acta Physiol Sin 2026; 78 (2): 452-462 (in Chinese with English abstract).