Revised: February 24, 2026
Accepted: April 17, 2026
Published online: June 27, 2026
Processing time: 147 Days and 6.7 Hours
Hepatic ischemia-reperfusion injury (IRI) is a critical pathological process as
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.
- Citation: Yang Y, Wu SL, Huang ZH, Dong MQ, Liu ZM, Xu M, Gao Y, Zhou WJ, Lin Y. LECT2/Tie1/Src signaling regulates the oxidative stress response in endothelial cells and liver ischemia-reperfusion injury. World J Hepatol 2026; 18(6): 119561
- URL: https://www.wjgnet.com/1948-5182/full/v18/i6/119561.htm
- DOI: https://dx.doi.org/10.4254/wjh.119561
Ischemia-reperfusion-induced liver injury (IRI) is a significant clinical problem following liver resection or trans
Endothelial cells secrete various signaling factors that induce inflammatory cell infiltration and cytokine production and play critical regulatory roles in ischemia-reperfusion injury. Liver sinusoidal endothelial cells (LSECs) are particularly vulnerable to ischemia-reperfusion injury, which disrupts their plasma membranes, causes nuclear vacuolation, and changes cell shape. During ischemia, LSECs and Kupffer cells exhibit edema, decreased nitric oxide bioavailability, and increased endothelin and thromboxane A2 production, leading to sinusoidal narrowing and microcirculatory dysfunction. During reperfusion, decreased nitric oxide levels, caused by reduced reactive oxygen species (ROS) production and clearance, regulate the extent of ischemia-reperfusion injury by modulating neutrophil adhesion, platelet aggregation, and hepatic stellate cell contraction. Dysfunctional LSECs activate Kupffer cells, promoting the release of ROS and proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), interferon-gamma, and IL-12. TNF-α stimulates intracellular adhesion molecule-1 expression on LSECs, facilitating neutrophil rolling, binding, and extravasation. It also induces P-selectin expression, further promoting neutrophil recruitment and adhesion to liver sinusoids. Extensive evidence indicates that endothelial cell damage is the initial factor leading to hepatic IRI, resulting in poor microcirculation, platelet activation, persistent vasoconstriction, upregulation of adhesion molecules, oxidative stress, Kupffer cell activation, neutrophil infiltration, and hepatocyte death[3-5].
The regulatory mechanisms underlying endothelial cell hypoxia-reoxygenation injury remain unclear. Leukocyte-derived chemotaxin-2 (LECT2) has been implicated in multiple physiological and pathological processes, including sepsis, diabetes, liver cancer, nonalcoholic fatty liver disease, and hematopoietic stem cell homeostasis. Previous work from our group identified LECT2 as a functional ligand for the orphan receptor Tie1 in endothelial cells, revealing a novel LECT2/Tie1 signaling axis that regulates liver fibrosis by modulating hepatic vascular function and remodeling[6,7]. Recently, we reported that LECT2 exacerbates liver IRI; however, the precise mechanism remains elusive. This study revealed that LECT2 binds to Tie1 and activates Src kinase, thereby regulating oxidative stress responses in endothelial cells under hypoxic conditions and play a critical role in liver IRI. Targeting the LECT2/Tie1 signaling pathway may have therapeutic potential for treating clinical liver IRI.
EA.hy926 cells (ATCC number: CRL-2922, RRID) were sourced from the American Type Culture Collection. These cells were maintained in DMEM (GIBCO, NY, United States) supplemented with 10% foetal bovine serum and incubated at 37 °C in a humidified environment containing 5% CO2. The identity of the cell lines has been verified.
His tagged recombinant LECT2 (rLECT2) protein and GST tagged recombinant Tie1-Ig3 protein were prepared as previous[6]. Src inhibitor dasatinib (BMS-354825) was purchased from Selleck, TX, United States (Cat. No. S1021). The following primary antibodies were used for western blotting: Anti-mTOR (7C10) (Cell Signaling Technology, MA, United States; Cat. No. 2983T), anti-Phospho-mTOR (Ser2448) (D9C2) (Cell Signaling Technology, MA, United States; Cat. No. 5536T), anti-Src (Cell Signaling Technology, MA, United States; Cat. No. 2109), anti-Phospho-Src (Y416) (Cell Signaling Technology, MA, United States; Cat. No. 2101), anti-LECT2 (SantaCruz, TX, United States; Cat. No. sc-398071), anti-β-actin (Proteintech, IL, United States; Cat. No. 20536).
Second antibodies: Goat Anti-Rabbit IgG (H + L) Secondary Antibody, HRP Conjugate, (Boster, China; BA1054); Goat Anti-Mouse IgG (H + L) Secondary Antibody, HRP Conjugate (Boster, China; BA1050).
LECT2 knockout mice (Lect2-/-) were produced using the CRISPR/Cas9 technique, with the genotype previously verified[6]. Genomic DNA was extracted and amplified using specific primers (forward: 5’-GTGAGACTTAGATGTGGGAAGTTCCTG-3’, reverse: 5’-CACCCTGAGGTATTCAGGCCATTAT-3’). All experiments utilized male mice, housed under specific-pathogen-free conditions with a 12-hour light-dark cycle and unlimited access to food and water. Animal protocols adhered to the United States Public Health Service Policy on Laboratory Animal Use and were approved by the Animal Ethics Committee of Nanfang Hospital, No. NFYY-2018-031.
For the hepatic ischemia-reperfusion model, male mice aged 6-8 weeks were fasted for 12 hours and anesthetized with isoflurane. A midline abdominal incision (3-5 cm) exposed the portal vein. The hepatic portal was separated from surrounding tissues, and a microvascular clamp blocked the portal triad structures (hepatic artery, portal vein, and bile duct) of the left and median lobes, confirmed by the lobes turning white. After 60 minutes of ischemia, reperfusion was initiated by removing the clamp, leading to an immediate color change in the median and left lateral lobes. The incision was closed with a two-layer suture technique, and disinfectant was applied to reduce infection risk. Mice were placed in heated, clean cages, and samples were collected at reperfusion times of 0.5, 6 and 24 hours.
Mouse liver tissues were fixed and sectioned into 2.5 mm thick slices. The sections were incubated in a citrate buffer (pH 6.0) at 120 °C for 5 minutes. Endogenous peroxidase activity was blocked by treating the sections with 0.3% H2O2 for 10 minutes. To block non-specific binding, the slides were incubated with 5% bovine serum albumin in phosphate buffered saline at 37 °C for 30 minutes. The sections were then incubated overnight at 4 °C with the primary antibody, anti-lymphatic vessel endothelial hyaluronic acid receptor 1 (anti-LYVE1, Abcam, United Kingdom; Cat. No. ab14917). Following this, the sections were incubated for 1 hour with an HRP-conjugated anti-rabbit IgG secondary antibody. Detection was performed using a DAB substrate kit (ORIGENE, United States; ZLI-9019).
Total RNA from EA.hy926 cells or mouse livers was extracted and reverse transcribed. The resulting complementary DNAs were used for polymerase chain reaction (PCR) with the SYBR-Green Master PCR Mix (Accurate Biology, Hunan Province, China). All PCR reactions were conducted in triplicate using the Quant Studio 3 qPCR System (Thermo Scientific, MA, United States; Quant Studio 3). The data for each sample were normalized to the endogenous glyceraldehyde-3-phosphate dehydrogenase (GAPDH) controls. Primers for quantitative PCR were as following. Human LECT2, forward: GCTGGTCTGATTTCTACCGCA, reverse: CCAGCAGAGCACAAGATGTC; human Tie1, forward: AATGC
EA.hy926 cells were cultured until they reached 80%-90% confluency. The complete medium in the culture dishes was then replaced with serum-free medium. These dishes were placed in an anaerobic jar, and an anaerobic gas-generating packet was added, along with an oxygen indicator. The jar was sealed tightly to ensure an anaerobic environment. After 8 hours of hypoxia, the samples were removed, the medium was replaced with complete medium, and the dishes were returned to the incubator. Cell samples were collected at 0, 1, 4, 8, 16, 32, 40, and 48 hours post-reoxygenation for further analysis.
Post-reoxygenation, the culture medium was discarded, and cell counting kit-8 reagent (Promega, WI, United States; Cat. No. G7570) diluted 1:9 with serum-free medium was added, 100 μL per well. Blank and control wells were included. Plates were incubated at 37 °C in a humidified incubator for 1 hour, protected from light. Absorbance at 450 nm was measured using a microplate reader to assess cell viability.
The LDH-Glo™ cytotoxicity assay (Promega, WI, United States; Cat. No. J2380) was performed to measure lactate dehydrogenase release due to cell membrane damage. Cells were collected into 1.5 mL Eppendorf tubes and centrifuged at 4 °C, 250 g for 5 minutes. Supernatants were used as test samples, with positive and blank controls set up. 50 μL of the sample and 50 μL of the reaction substrate were added to each well and incubated on a shaker in the dark for 25 minutes. Subsequently, 50 μL of stop solution was added to each well and incubated for an additional minute on a shaker in the dark. Absorbance at 490 nm was measured using a microplate reader to evaluate cytotoxicity.
Total superoxide dismutase (SOD) activity was measured using the Total SOD Activity Detection Kit (Beyotime, China; Cat. No. S0101M). Cells were washed once with 4 °C phosphate buffered saline buffer and lysed with 200 μL of protein lysis buffer. The lysate was transferred to a 1.5 mL Eppendorf tube with two steel beads, agitated in a tissue grinder at 4 °C for 10 seconds, and centrifuged at 4 °C, 12000 rpm for 5 minutes. The supernatant was used for the SOD activity assay.
Intracellular ROS levels were measured using an ROS assay kit (Beyotime, China; S0033S) according to the manu
Cell apoptosis was detected using the TUNEL Cell Apoptosis Detection Kit (Beyotime, China; Cat. No. C1098). This kit labels the terminal end of nucleic acids to detect DNA fragmentation, a hallmark of apoptosis. The assay was performed according to the manufacturer’s instructions to ensure accurate and reliable results.
Data were analyzed using GraphPad Prism 8 software. Comparisons between two groups were performed using unpaired or paired Student’s t-test, as appropriate. For comparisons involving multiple treatment groups against a control group, one-way or two-way ANOVA was used, followed by Dunnett’s multiple comparison test. All data are presented as mean ± SEM. A P value < 0.05 was considered statistically significant.
Small interfering RNA was employed to silence LECT2 expression in EA.hy926 cells (Figure 1A and B). Following 8 hours of hypoxia, cell proliferation, oxidative stress, and cytotoxicity markers were assessed at various reoxygenation time points. Compared with the control group, LECT2 knockdown in EA.hy926 cells resulted in significantly increased proliferation at 1 hour post-reoxygenation (Figure 1C). Furthermore, LECT2 knockdown cells exhibited a markedly reduced oxidative stress response compared to control cells during the reoxygenation phase (Figure 1D and E). Cytotoxicity, measured by lactate dehydrogenase release, was significantly lower in LECT2 knockdown cells compared to controls (Figure 1F). These results suggest that silencing the LECT2 gene enhances the resilience of EA.hy926 cells to hypoxia-reoxygenation injury.
Human rLECT2 was used at three concentration gradients, which were added to the cell culture medium immediately after hypoxia-reoxygenation. Various indicators were measured at specific timepoints. The results demonstrated that the addition of rLECT2 protein led to decreased proliferation capacity in EA.hy926 cells (Figure 1G), exacerbated oxidative stress response (Figure 1H and I), and increased expression of cytotoxicity markers (Figure 1J).
Our previous studies identified LECT2 as a functional ligand of the receptor Tie1. To investigate whether LECT2 exerts its effects through Tie1[6], we used small interfering RNA to knockdown Tie1 expression in EA.hy926 cells (Figure 2A and B). The results showed that Tie1 knockdown alone did not affect hypoxia-reoxygenation injury in EA.hy926 cells. However, rLECT2 significantly increased hypoxia-reoxygenation injury in control EA.hy926 cells but did not exacerbate injury in Tie1 knockdown EA.hy926 cells (Figure 2C-E).
Our previous research demonstrated that LECT2 directly binds to the Tie1-Ig3 segment. The recombinant Tie1-Ig3 segment protein (Tie1-Ig3) can block the LECT2/Tie1 interaction, thereby inhibiting downstream signal transduction[6]. We used the Tie1-Ig3 to observe changes in various indicators at specific timepoints. The results showed that the addition of the Tie1-Ig3 reduced the hypoxia-reoxygenation injury caused by rLECT2 in EA.hy926 cells (Figure 2F-H).
Src family kinases are key mediators of endothelial barrier dysfunction and inflammatory responses, and have been implicated in various models of IRI. The mTOR pathway, a downstream effector of PI3K/Akt signaling, is also known to intersect with Src in regulating endothelial cell survival and oxidative stress responses[8,9]. However, whether these kinases are involved in LECT2/Tie1-mediated endothelial injury during hepatic IRI remains unknown. To investigate this, we examined the activation of mTOR and Src in EA.hy926 cells subjected to hypoxia-reoxygenation. The results showed that in the hypoxia-reoxygenation injury model of EA.hy926 cells, LECT2 knockdown did not alter the protein levels and phosphorylation levels of mTOR, but reduced the phosphorylation levels of Src without affecting its protein levels (Figure 3A). Conversely, rLECT2 treatment did not affect mTOR protein or phosphorylation levels but did increase Src phosphorylation levels (Figure 3B). Tie1-Ig3 treatment similarly reduced Src phosphorylation levels (Figure 3C).
To determine the role of Src kinase activation in LECT2/Tie1-mediated regulation of hypoxia-reoxygenation injury in EA.hy926 cells, the Src inhibitor dasatinib was applied. Dasatinib significantly inhibited rLECT2-induced Src phosphorylation (Figure 3D). Furthermore, dasatinib blocked the effects of rLECT2 on cell proliferation, oxidative stress, and cytotoxicity (Figure 3E-G) and reduced rLECT2-induced expression of the inflammatory marker TNF-α (Figure 3H). These results indicate that LECT2 regulates hypoxia-reoxygenation injury in EA.hy926 cells by activating Src.
Src-mediated endothelial dysfunction is a critical initiator of vascular inflammation in vivo. Upon activation, Src promotes endothelial hyperpermeability and upregulation of adhesion molecules, facilitating leukocyte recruitment and transendothelial migration. Infiltrating leukocytes then amplify local inflammation through release of ROS and pro-inflammatory cytokines, which in turn can further activate Src signaling in endothelial cells via direct cell-cell interactions, creating a positive feedback loop that perpetuates tissue injury[10-12].
To investigate the role of LECT2 in vivo, we subjected Lect2-/- mice to a hepatic IRI model. Compared with wild-type control mice, Lect2-/- mice exhibited reduced apoptosis and decreased expression of IL-1b, IL-6, and TNF-α, indicating lower levels of liver injury and inflammatory factors (Figure 4A-F). Normal hepatic sinusoidal endothelial cells highly express LYVE1, whereas damaged cells have reduced or absent LYVE1 expression. Lect2-/- mice exhibited significantly higher LYVE1 expression after ischemia-reperfusion compared to wild-type control mice (Figure 4G and H), indicating that endothelial cells in Lect2-/- mice are less damaged during ischemia-reperfusion.
In this study, we demonstrate that LECT2 exacerbates hypoxia-reoxygenation injury in endothelial cells by binding to Tie1 and activating Src kinase, thereby aggravating hepatic IRI. LECT2 knockdown reduced endothelial cell damage, whereas recombinant LECT2 exacerbated it. Tie1 knockdown, blockade of LECT2/Tie1 binding using recombinant Tie1-Ig3 protein, and Src inhibitors all mitigated hypoxia-reoxygenation injury in endothelial cells. LECT2 gene knockout mice exhibited reduced liver IRI and endothelial cell injury. The results of this study revealed a novel mechanism by which the LECT2/Tie1/Src signaling pathway regulates hypoxia-reoxygenation injury in endothelial cells, providing new targets and strategies for treating hepatic IRI.
Hepatic IRI progresses through four stages: The ischemia-hypoxia stage, early reperfusion stage, reperfusion injury stage, and repair stage. Initially, the liver is exposed to a hypoxic environment, with LSECs as the primary cells to suffer initial damage. Their barrier function is compromised, vascular permeability increases, and hepatocytes are immediately damaged, with cellular activities gradually becoming disordered. During the early reperfusion stage, oxidative stress intensifies, with massive ROS production further aggravating LSEC and hepatocyte damage, even leading to cell death. In the subsequent injury stage, macrophages are activated, neutrophils accumulate in large numbers, and a cascade of inflammatory responses occurs, exacerbating hepatocyte damage and death. Finally, during the repair stage, hepatic stellate cells and immune cells jointly promote liver recovery[13-18]. In this study, hematoxylin and eosin staining was used to assess and quantify necrotic areas, and TUNEL staining was performed to label apoptotic cells, demonstrating that deletion of the LECT2 gene significantly reduced necrosis and apoptosis during hepatic IRI.
Endothelial cells are the first to be damaged after ischemia-reperfusion or cellular hypoxia-reoxygenation. LSEC dysfunction following IRI is the initial factor leading to hepatic IRI, determining subsequent vascular contraction, oxidative stress, inflammatory responses, and hepatocyte death[3,4]. Our previous studies demonstrated that LECT2/Tie1 signaling regulates endothelial cell migration and tubule formation. Here, we further show that LECT2/Tie1 signaling activates Src kinase, regulating hypoxia-reoxygenation injury in endothelial cells. Src, encoded by the SRC gene, is a nonreceptor tyrosine kinase specific to tyrosine residues in the cytoplasm. Tyrosine kinases are usually regulated, with low basal activity, and are transiently activated by specific stimuli[19]. The major phosphorylation sites of Src include tyrosine 416, which leads to autophosphorylation activation, and tyrosine 527, which inhibits C-terminal Src kinase phosphorylation. Src phosphorylation at tyrosine 416 enhances kinase activity[10]. Src plays a crucial role in regulating cell proliferation, differentiation, survival, metabolism, and other essential cellular functions. It is vital for barrier regulation and endothelial cell angiogenesis. During hepatic IRI and cellular hypoxia-reoxygenation injury, the balance between Src phosphorylation and dephosphorylation affects inflammatory responses and apoptosis. ROS levels can activate Src protein tyrosine kinases, dephosphorylate tyrosine phosphatases, inhibit their activity, and prolong Src protein tyrosine kinase activity[11,12]. Src family kinases are regulated by multiple receptors, including protein tyrosine kinase receptors. Tie1 is a tyrosine kinase that plays an essential role in angiogenesis and homeostasis[6,20-23]. Further research is required to determine how Tie1 regulates Src kinase activation.
Our previous work identified LECT2 as a functional Tie1 Ligand that disrupts Tie1/Tie2 heterodimerization and promotes Tie2 homodimerization[6]. This raises the possibility that Tie2 may also contribute to LECT2-mediated signaling in hepatic IRI. Systematic evaluation of Tie2 expression and activation in response to LECT2 stimulation represents an important direction for future studies to fully delineate the angiopoietin-Tie interplay in this context.
The translational potential of targeting the LECT2/Tie1/Src axis in hepatic IRI is supported by several factors: LECT2 is a secreted hepatokine amenable to antibody neutralization, Tie1 exhibits endothelial-specific expression, and Food and Drug Administration-approved Src inhibitors (e.g., dasatinib) are clinically available for potential repurposing. However, several limitations warrant consideration. First, species-specific differences in LECT2/Tie1 signaling between rodents and humans require validation in human tissues and large-animal models. Second, systemic Src inhibition carries off-target risks given Src’s pleiotropic roles in cell proliferation, survival, and metabolism across multiple cell types. Third, our use of the EA.hy926 cell line, while useful for mechanistic studies, may not fully recapitulate primary LSEC phenotypes, necessitating future validation in primary cells.
Our proof-of-concept study demonstrates that Tie1-Ig3 recombinant protein effectively blocks LECT2/Tie1 binding and alleviates endothelial injury. While these findings suggest that disrupting this interaction may represent a therapeutic strategy, we acknowledge that this approach requires extensive further validation. Future efforts should focus on optimizing Tie1-Ig3, evaluating its efficacy and safety in vivo, and assessing potential off-target effects. Concurrent screening for small-molecule inhibitors targeting the LECT2/Tie1 interface may provide alternative therapeutic avenues. Until such rigorous preclinical validation, including assessment of specificity, bioavailability, and long-term safety, is completed, conclusions regarding clinical applicability remain speculative.
In conclusion, this study demonstrates that the LECT2/Tie1/Src signaling axis plays a critical role in regulating oxidative stress response in endothelial cell and liver hepatic ischemia-reperfusion injury. Using a combination of in vitro and in vivo models, we establish that LECT2 exacerbates hypoxic damage by binding to Tie1 and activating Src. In contrast, disruption of this pathway, through genetic knockout, receptor blockade, or kinase inhibition, effectively mitigates cellular and organ injury. These findings not only reveal a previously unrecognized mechanism underlying endothelial dysfunction in liver IRI but also highlight the therapeutic potential of targeting the LECT2/Tie1 interface. Further development of specific inhibitors or biologics directed against this pathway may offer a promising strategy for clinical intervention in liver transplantation, resection, and other ischemia-associated hepatic conditions.
We thank Central Laboratory, Southern Medical University for providing facilities and technical support.
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