Revised: February 24, 2026
Accepted: April 17, 2026
Published online: June 27, 2026
Processing time: 141 Days and 3.4 Hours
Hepatic ischemia-reperfusion injury (IRI) is a critical pathological process associated with trauma, sepsis, and liver surgeries, including transplantation. During reperfusion, oxidative stress in sinusoidal endothelial cells triggers cell death, however, the underlying regulatory mechanisms remain poorly defined. Previous studies have implicated leukocyte-derived chemotaxin-2 (LECT2) in various diseases and identified it as a ligand for the orphan receptor Tie1, yet its role in endothelial cell injury during liver IRI remains unclear.
To investigate whether LECT2 exacerbates liver IRI by regulating oxidative stress in endothelial cells through the Tie1/Src signaling pathway and to evaluate the therapeutic potential of targeting this axis.
In vitro hypoxia-reoxygenation injury was modeled in EA.hy926 endothelial cells, followed by LECT2 knockdown or recombinant LECT2 treatment, Tie1 silencing, and Tie1-Ig3 segment protein treatment to block LECT2/Tie1 binding. Src kinase activity was inhibited using dasatinib. Cell viability, oxidative stress, cytotoxicity, and signaling pathway activation were assessed. In vivo, LECT2 knockout mice underwent hepatic ischemia-reperfusion, while injury markers, inflammatory cytokines, and endothelial damage were evaluated.
LECT2 knockdown reduced oxidative stress and endothelial cell damage following hypoxia-reoxygenation, whereas recombinant LECT2 exacerbated these effects. Disruption of LECT2/Tie1 binding, via either Tie1 knockdown or Tie1-Ig3 treatment mitigated injury. Mechanistically, LECT2 activated Src kinase phosphorylation in a Tie1-dependent manner, and Src inhibition reversed LECT2-induced cell damage. In mice, LECT2 deletion attenuated liver IRI, decreased apoptosis and inflammation, and better preserved sinusoidal endothelial integrity.
The LECT2/Tie1/Src signaling axis plays a critical role in regulating oxidative stress and endothelial cell injury during hepatic ischemia-reperfusion. Targeting the LECT2/Tie1/Src signaling pathway may offer a novel thera
Core Tip: This study elucidates a novel signaling mechanism in which leukocyte-derived chemotaxin-2 exacerbates hepatic ischemia-reperfusion injury by binding to Tie1 and activating Src kinase, thereby amplifying oxidative stress and endothelial cell damage. Targeting the leukocyte-derived chemotaxin-2/Tie1/Src axis represents a promising therapeutic strategy for mitigating liver ischemia-reperfusion injury, offering potential translational applications in liver surgery and transplantation.