IDDF2024-ABS-0273 LCN2 promotes ferroptosis and induces impairment of intestinal barrier function in ulcerative colitis by regulating ALOX15-mediated lipid peroxidation

Background

Ulcerative colitis (UC) is a chronic inflammatory condition of the intestinal tract that affects the rectum and colon. Ferroptosis is a type of cell death that is triggered by an excess of peroxidized lipids on cell membranes and is dependent on iron. The goal of this study was to investigate the underlying molecular mechanisms through which the Lipocalin2 (LCN2)-Arachidonic acid 15-lipoxygenase (ALOX15) axis controls ferroptosis in UC.

Methods

We conducted experiments to investigate the impact of adding a lipid peroxidation inhibitor (Trolox) on ferroptosis and the loss of intestinal barrier in UC cells and animal models. Our study utilized lipid metabolomics, transcriptomics, an ALOX15 inhibitor (PD146176), ALOX15 knockdown/overexpression cell lines, and transgenic mice to examine the role of ALOX15 in UC. Furthermore, we analyzed the LCN2-ALOX15 axis to understand its regulatory function in UC by employing computerized virtual molecular docking, LCN2 knockdown/overexpressing cell lines, and transgenic mice.

Results

Our research identified that lipid peroxidation in intestinal epithelial cells is a crucial factor in causing ferroptosis and disrupting the intestinal barrier in ulcerative colitis (UC). Through analyzing transcriptomics and lipid metabolomics, we discovered that ALOX15 plays a key role in regulating lipid peroxidation in IECs in UC models. Treatment with PD146176 effectively suppressed lipid peroxidation and ferroptosis in intestinal epithelial cells. Additionally, we confirmed that LCN2, an upstream regulator of ALOX15, promotes ferroptosis in IECs and contributes to the impairment of the intestinal barrier in UC by influencing lipid peroxidation, iron accumulation, intestinal barrier function, and the inflammatory response in intestinal epithelial cells.

Conclusions

This study has revealed that the LCN2-ALOX15 axis is instrumental in controlling lipid peroxidation, driving ferroptosis in IECs, and causing dysfunction in the intestinal barrier of individuals with UC (IDDF2024-ABS-0273 Figure 1. LCN2 controls the ferroptosis of intestinal epithelial cells through ALOX15, leading to the impairment of intestinal barrier function in ulcerative colitis). These results present fresh perspectives and avenues for the advancement of clinical drug treatments for UC.