In the early phase of HIRI, DAMPs activate resident immune cells in the liver, particularly Kupffer cells and LSECs, which subsequently induce the production of various inflammatory mediators such as chemokines (CXCL1, CXCL2), cytokines (TNF-α, IL-1β) and ROS (64). This cascade of reactions collectively promotes the directed recruitment of neutrophils to the liver and initiates a systemic inflammatory response. Notably, the extent of neutrophil recruitment is markedly associated with the duration of ischemia, the longer the ischemic period, the more intense the local and systemic inflammatory responses, ultimately leading to aggravated liver injury.

During the HIRI process, leukotriene B4 (LTB4) is one of the earliest neutrophil chemokines to be released and its strong chemotactic effect plays a crucial role in the early inflammatory response (65). In addition, FMIT released from mitochondria binds to the formyl peptide receptor 1 (FPR1) receptor on the surface of neutrophils during cell necrosis, promoting their migration to the necrotic area. Neutrophils play a role in HIRI in the initial immune response and by activating the complement system, which further enhances the inflammatory response. C5a in the complement system is one of the strongest chemotactic factors (65) and promotes neutrophil recruitment and infiltration to the damage site by binding to the C5aR1 receptor on the neutrophil surface (66). Zhang et al (67) reduced neutrophil recruitment and ROS production by using single-stranded oligonucleotides with high affinity for C5a, coupled to nanoparticles, thus alleviating inflammation and damage associated with HIRI.

LSECs upregulate the expression of CXCL1 during HIRI, which not only promotes neutrophil NETs formation but also exacerbates the formation of liver sinusoids and the occurrence of portal hypertension (68). However, chemokines alone are insufficient for efficient neutrophil recruitment. For optimal chemotactic effects, the concentration of chemokines must be maintained within a precise range, a process depends on the expression of glycosaminoglycans (GAGs) on LSECs (69). GAGs can bind chemokines via their sulfated domains, anchoring them to the endothelial surface and thereby establishing and maintaining a local high-concentration chemokine gradient, which is essential for the specific recruitment of neutrophils (70,71). Research shows that blocking the expression of heparan sulfate significantly inhibits chemokine-mediated neutrophil migration (72); similarly, disrupting the interaction between GAGs and chemokines effectively suppresses neutrophil extravasation in gout models (73). In summary, chemokines, cytokines, the complement system and GAGs form a synergistic regulatory network that precisely controls the activation and recruitment of neutrophils in the early stage of HIRI.

After reperfusion, neutrophils are activated and adhere to LSECs to enter the injury area. The unique structure of LSECs determines the specificity of neutrophil migration. Unlike capillaries in other organs, LSECs possess a porous structure, have relatively little subendothelial basement membrane material and lack intercellular junctions. These structural characteristics allow large molecules such as lipoproteins to pass through, but prevent the passage of chylomicrons (74). Additionally, LSECs in the liver do not express Weibel-Palade bodies and are devoid of E- and P-selectins (75). As a result, selectin-mediated neutrophil rolling is not observed on LSECs (76). This feature indicates that the accumulation of neutrophils in the hepatic sinusoids is less dependent on these adhesion molecules. In vivo microscopic observations show that ~80% of neutrophils adhere to LSECs, while 20% adhere to post-sinusoidal venules, highlighting the critical role of LSECs in adhesion (77). Among these, CD44-mediated interactions between hyaluronic acid (HA) receptors play an important role in neutrophil adhesion to LSECs. The binding of CD44 to the extracellular matrix (ECM) of LSECs enhances neutrophil contact with the liver microenvironment (78,79). In models of endotoxin-induced liver injury, blocking the CD44-HA interaction markedly inhibits neutrophil adhesion in the sinusoids but does not markedly affect adhesion in post-sinusoidal venules. This indicates that the CD44-HA pathway has a specific role in HIRI. CD44 activates the p38 MAPK and PI3K/Akt pathways, mediates cytoskeletal rearrangement and strengthens firm adhesion, while upregulating integrin expression to stabilize neutrophil-endothelial interactions (78).

In HIRI models, neutrophil interactions with LSECs involve the binding of the integrin molecule Mac-1 (CD11b/CD18) with ICAM-1 on LSECs. After ischemic injury, LSECs can sense DAMPs through Toll-like receptor 9, thereby directly inducing the release of IL-1β and IL-18. The upregulation of these cytokines further enhances ICAM-1 expression, promoting neutrophil migration to the liver sinusoidal spaces (80).

Neutrophils migrate into the liver parenchyma via TEM, a process that occurs mainly through paracellular or transcellular routes, with the paracellular pathway dominating in peripheral circulation (81). A key step in TEM is the binding of β2-integrin (CD11b/CD18) to VCAM-1 (82). Under acute inflammatory conditions, LSECs rapidly activate the endothelial Notch signaling pathway (83), increasing the expression of TNF-α and IL-33, which further exacerbates liver damage (84).

Additionally, after neutrophils cross the vascular endothelium, their migration within the ECM depends on the dynamic balance of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). MMPs are responsible for hydrolyzing ECM components, while TIMPs regulate MMP activity. Among them, gelatinases (MMP2-MMP9) play an important role in HIRI (85). Fibronectin is a key component of the ECM glycoprotein family and activates the integrin α4β1 receptor on neutrophils in HIRI mice, leading to the production of MMP9. Inhibitors of MMP9 markedly reduce neutrophil infiltration and alleviate liver damage. Alterations in the MMP-TIMP balance are associated with pathological processes involving ECM degradation, such as tumor invasion, angiogenesis and tissue repair. Duarte et al (86) verified that animals lacking TIMP1 suffered more severe liver dysfunction and tissue damage. In this model, the mortality rate of TIMP1 double-knockout mice following reperfusion was 60%, while all wild-type mice survived (86). Additionally, the lack of TIMP1 was associated with increased MMP9 activity, which facilitated neutrophil migration across the vascular barrier during liver IRI. Indeed, TIMP double knockout mice exhibited marked neutrophil infiltration in the liver, accompanied by upregulation of proinflammatory mediators such as TNF-α, IFN-γ and inducible nitric oxide synthase. Therefore, MMPs and TIMPs play crucial roles in maintaining liver homeostasis and can serve as therapeutic targets for improving liver injury.

Beyond TEM, increasing evidence with the advance of imaging techniques suggests that neutrophils can also undergo rTEM (63). Neutrophils can migrate within tissues and subsequently clear the infection site through this mechanism. However, dysregulation of this process may trigger systemic inflammatory responses. The mechanisms of rTEM are still under active investigation. Some studies have identified potential regulatory factors that play key roles in neutrophil rTEM. For example, increased levels of chemokines ultimately lead to neutrophil migration in the opposite direction along the microvenular wall (87), suggesting that the concentration of chemotactic factors is one of the main determinants of accelerating neutrophil rTEM. Furthermore, dynamic regulation of chemokine receptor expression on the neutrophil surface or its sensitivity to corresponding ligands is critical for neutrophil rTEM (88). In addition to these chemokine- and receptor-mediated events, junctional adhesion molecule-C (JAM-C) is the most widely studied molecule regulating neutrophil rTEM and has been widely expressed on endothelial cells (EC). JAM-C knockout mice exhibited increased rTEM neutrophils, with more than 50% of total transendothelial migration events, compared with ~10% observed in wild-type animals (80). This group also described the JAM-C-mediated leukocyte rTEM regulation mechanism mediated by the LTB4 and NE axis (89).

It is worth noting that, since neutrophil rTEM functions by clearing excess neutrophils from local tissues, regulating T and B cell proliferation, NET formation and inducing systemic inflammation and immune system interactions (81,90-92), targeting neutrophil rTEM may represent a new therapeutic strategy to address inflammation. Future research strategies may focus on modulating chemokine gradients, stabilizing endothelial junctions, or targeting the MMP-TIMP axis to achieve this balance, offering novel avenues for treating HIRI and other inflammatory diseases.

Another important function of neutrophils in HIRI is the formation of NETs. NETs consist of an extracellular scaffold of nuclear DNA loaded with histones and granular proteins such as NE and MPO. The mechanism of NET formation involves NADPH oxidase- and peptidylarginine deiminase 4 (PAD4)-mediated citrullination of histones, translocation of neutrophil NE and MPO to the nucleus, chromatin decondensation and extracellular DNA release promoted by proteolysis of histones.

Neutrophils produce and release NETs through a process called NETosis. While NETs serve as a beneficial defense strategy against pathogens by trapping and combating bacteria, fungi and protozoa (92), in sterile inflammation such as HIRI, 'suicidal NETosis' (that is, neutrophil programmed death associated with NET release) predominantly occurs. By exposing intracellular proteins to the extracellular space, NETosis promotes the presentation of autoantigens and the release of DAMPs, thereby amplifying the ongoing inflammatory response. Research (93) shows that in liver transplantation-associated HIRI, plasma levels of NET markers were markedly elevated in LT recipients, peaking at the end of transplantation and correlating with coagulation activation. Compared with healthy controls, levels of the more specific NET marker MPO-DNA complexes were already markedly increased at the beginning of transplantation (94). Besides plasma, NETs were detected in liver tissue 30 min after reperfusion. Excessive NET formation exacerbates tissue damage.

In recent years, the dual role of neutrophils in sterile inflammation, both driving tissue injury and promoting inflammation resolution and tissue repair, has garnered widespread attention. Traditionally viewed as 'first responders' that promote inflammation and tissue destruction, growing evidence indicates that neutrophils possess high functional plasticity. Under specific microenvironmental regulation, they can shift toward anti-inflammatory, pro-repair phenotypes and participate in steering HIRI from a 'damage-dominant' to a 'repair-dominant' transition. In liver-related injury models, the reparative functions of neutrophils have been preliminarily revealed. For instance, Wang et al (7) found that in a fully repaired sterile thermal liver injury model, neutrophils also penetrated the injury site, performing critical tasks such as dismantling damaged vessels and creating channels for new vascular regrowth. These neutrophils performing key repair functions neither died nor were phagocytosed. Instead, they returned to the circulation via rTEM, likely became inactivated or reprogrammed and then migrated selectively to the bone marrow via CXCR4 to end their life cycle. Deng et al (8) further elucidated how the post-injury liver signals the bone marrow to release neutrophils and how reparative neutrophils signal hepatocytes to re-enter the cell cycle. Using liver-specific leukemia inhibitory factor receptor (LIFR) knockout mice, the authors demonstrated that hepatocyte LIFR promotes the secretion of CXCL1 and cholesterol in a STAT3-dependent manner, recruiting and activating neutrophils. These neutrophils, in turn, secrete the hepatocyte mitogen HGF, accelerating liver injury repair and regeneration. Lin et al (9) discovered that during allogeneic tissue transplantation (mouse heart, kidney and human cardiac tissue), neutrophils are indispensable for creating new vascular networks, further confirming their pivotal role in tissue repair. Marques et al (10) found that compared with Kupffer cell depletion, neutrophil depletion using anti-Ly-6G alleviated acetaminophen-induced liver injury. In this liver injury model, a small number of neutrophils contributed to the clearance of cellular debris, whereas a large number enhanced liver injury and inflammation. Thus, the role of neutrophils in this process is determined by the quantity of toxic substances in the liver and the number of infiltrating neutrophils. Consequently, how to regulate neutrophil function to promote the shift from injury to repair has become a focus of our attention.

Similar to macrophages, the diverse biological functions of neutrophils are influenced by timing and specific tissue environments. Analogous to the ability of macrophages to polarize toward M1/M2 phenotypes under different stimuli (95), studies indicate that specific microenvironments can also drive neutrophils toward distinct phenotypes such as N1/N2 (60,61,96,97). Currently, N1 and N2 neutrophil populations are primarily defined by their functional phenotypes, based on their capacities for degranulation, cytokine release and migration. The same phenotypes have been identified as pro-inflammatory (N1) and anti-inflammatory (N2) neutrophils. Mihaila et al (98) characterized phenotypic and functional differences between N1 and N2 neutrophils in vitro based on transcriptomics and functional assays. The authors found that compared with N2 neutrophils, N1 neutrophils exhibited higher levels of ROS and oxidative burst, greater MPO and MMP-9 activity and stronger chemotactic responses. N1 neutrophils also showed elevated expression of NADPH oxidase subunits and activation of signaling molecules ERK and the p65 subunit of NF-κB. Furthermore, they identified for the first time that the alarmin S100A8/9, abundantly secreted by activated neutrophils, serves as a critical promoter of the aggressive pro-inflammatory N1 phenotype through an autocrine mechanism.

Although no direct studies have explicitly identified N2-type neutrophils or systematically resolved their polarization trajectory in HIRI models, multiple cross-disease model studies provide strong support for this hypothesis (11,12,99). In the early phase of HIRI, initially infiltrating neutrophils mostly exhibit an 'N1-like' phenotype with high activity, ROS production and strong chemotactic capacity, releasing mediators such as MPO, NE and NETs that exacerbate oxidative stress and microcirculatory dysfunction. As reperfusion time extends, the microenvironment gradually shifts from pro-inflammatory to pro-repair and some neutrophils begin to display anti-inflammatory, pro-angiogenic and immunomodulatory characteristics, suggesting the occurrence of functional polarization. This functional duality makes neutrophil polarization a central node in the 'injury-resolution balance,' directly influencing the prognosis of HIRI. This theory has been corroborated in ischemia models of the heart and brain. In a myocardial infarction model, the predominant neutrophil subset in the infarct area was N1-type neutrophils rich in pro-inflammatory factors, peaking on day 1; subsequently increased N2-type neutrophils corresponded to the anti-inflammatory phenotype after infarction (11). In a mouse stroke model, peripheral blood neutrophil counts peaked at 12 h after cerebral ischemia, with peak brain injury occurring 1-2 days later. In stroke lesions, neutrophil clearance peaked 2 days post-stroke and extracellular traps were mostly detected 2-3 days after stroke. Among neutrophils infiltrating stroke lesions, N2-phenotype neutrophils promoted macrophage-mediated neutrophil clearance. These processes are highly similar to the pathological progression of HIRI, that is, the dynamic transition from early inflammatory storm to later repair and regeneration (12). Therefore, it is reasonable to hypothesize that a similar neutrophil phenotypic switch exists in HIRI, though it has not yet been systematically identified and deeply explored.

Currently, research on neutrophil polarization and repair primarily focuses on cancer models (100). However, the role of neutrophil polarization in tissue repair is also gradually emerging in non-neoplastic diseases. In a mouse brain inflammation model, rosiglitazone treatment shifted the neutrophil population toward an N2 phenotype, suppressing inflammatory responses, promoting neutrophil clearance and reducing brain injury (101).

In summary, although direct evidence for N1/N2 polarization switching in HIRI is currently lacking, multisystem, cross-disease studies consistently indicate that neutrophil function is highly dynamic and context-dependent. Their shift from 'pro-inflammatory effectors' to 'repair coordinators' may be a critical node determining the prognosis of HIRI. Therefore, promoting neutrophil polarization toward an N2-like phenotype could be a potential therapeutic strategy to alleviate HIRI and foster liver regeneration. Future research should focus on the specific mechanisms of N1/N2 polarization, including whether a polarization process exists and whether it is driven by 'transcriptional reprogramming' of existing neutrophils or by 'epigenetic remodeling' of newly recruited cells due to environmental changes.

Chemokine receptors, as core targets regulating neutrophil recruitment, have become an important direction in HIRI treatment. Chemokines such as CXCL1 and CXCL2 precisely guide neutrophils toward inflammatory sites by binding to the CXCR2 receptor. Currently, drug development targeting CXCR2 has achieved phased progress. In animal models, the dual-target inhibitor Ladarixin (targeting CXCR1 and CXCR2) has been shown to effectively block neutrophil infiltration across the vascular basement membrane while preserving their rolling and adhesion functions, thereby suppressing the inflammatory response (102). Furthermore, small-molecule CXCR2 antagonists such as Repertaxin, Navarixin, Danirixin and AZD5069 have also demonstrated potential in reducing neutrophil recruitment in animal disease models (103), showing significant efficacy particularly in sustained inflammatory conditions such as cystic fibrosis, severe asthma and chronic obstructive pulmonary disease (COPD). It is noteworthy that CXCR2-selective inhibitors have not caused significant impairment to neutrophil host defense functions, providing a key basis for their safety profile. Most of these drugs are still in clinical development (such as, Phase II trial NCT001006616 for COPD) (104), indicating that preliminary human safety data are being accumulated. However, no clinical trials targeting HIRI have yet been reported. Clinical investigations of CXCR2-selective inhibitors for other diseases are ongoing, such as studies on their role in combination with oseltamivir for influenza treatment (105). These preliminary results have validated the feasibility of the strategy to inhibit neutrophil recruitment by targeting chemokine receptors.

The complement system represents another key regulatory network for neutrophil recruitment, demonstrating unique advantages in mitigating HIRI when suppressed. C3a, C5a and the membrane attack complex (MAC) play central roles in liver IRI by activating the complement cascade and exacerbating tissue damage. Preclinical studies have confirmed that multi-strategy interventions targeting the complement system (such as blocking C3, C5, or enhancing endogenous regulatory mechanisms) can markedly improve liver injury outcomes. For example, the humanized monoclonal antibody Eculizumab (targeting C5), an approved drug, has established its safety profile in diseases such as paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome (106). However, its application for human HIRI has not been reported. For mouse models, anti-C5 monoclonal antibody (BB5.1) treatment not only reduced ALT levels and inhibited the expression of inflammatory mediators such as IL-6 and TNF-α, but also provided cellular protection by reducing neutrophil infiltration and oxidative stress at both early (2 h) and late (6 h) reperfusion stages (66). Furthermore, C3 inhibitors such as the compstatin analog AMY-101, by blocking C3 convertase, reduced kidney damage and systemic inflammation in hemorrhagic shock models. The mechanism involves inhibiting the production of anaphylatoxins, regulating Kupffer cell phagocytosis and blocking the complement positive feedback loop (107,108). A promising strategy involves using recombinant regulatory molecules to mimic endogenous regulatory mechanisms [such as soluble CR1 (sCR1) and CR2-CD59 fusion proteins] (109,110), which can precisely modulate complement activation without inducing immunosuppression. In liver IRI models, these approaches have shown the potential to reduce MAC deposition, protect microvascular integrity and preserve C3a/C5a-mediated regenerative signaling. While clinical evidence for complement inhibitors in cardiac surgery has accumulated (110), targeted clinical trials are still needed to validate efficacy in humans for hepatic IRI. Nevertheless, existing data strongly support their potential as breakthrough therapies for surgery- and transplant-associated liver injury.

Neutrophil adhesion and migration depend on interactions with adhesion molecules on endothelial cells, such as ICAM-1 and P-selectin. Therefore, anti-adhesion molecule therapy has become an important strategy for targeting neutrophils. ICAM-1 blockers reduce inflammation in rat pancreatic transplant models and improve microvascular perfusion (111). In rat models, NE inhibitor sivelestat sodium inhibits neutrophil migration to the vessel wall, reducing HIRI (112). In 2025, Xia et al (113) developed a macrophage membrane-disguised manganese-based anti-aging nanzyme (MB@LM) for targeted delivery and oxidative stress relief in acute kidney injury (AKI) treatment. MB@LM selectively targets damaged kidney tissue overexpressing adhesion molecules such as ICAM-1 and VCAM-1, promoting enhanced accumulation at the injury site. In an AKI mouse model, MB@LM treatment markedly reduced renal injury, restored microvascular perfusion assessed by ultrasound imaging and alleviated inflammation, demonstrating marked therapeutic efficacy. The present review provides strong support for the treatment of liver injury.

In addition to conventional systemic immunosuppressive therapies, some studies have proposed local immunosuppressive strategies that involve the topical administration of immunosuppressants or regulatory factors to reduce neutrophil activation. For example, the use of specific pro-resolving mediators such as lipoxin A4 (LXA4) can inhibit neutrophil activation and migration (114,115), thereby alleviating hepatic inflammatory responses. LXA4 acts by activating the ALX/FPR2 receptor, suppressing ROS production and NETs formation by neutrophils and thus reducing liver inflammation induced by reperfusion injury. The LXA4/FPR2 signaling pathway mitigates ferroptosis in alveolar epithelial cells during lung IRI via an NRF2-pathway-dependent mechanism (116), which may offer a novel therapeutic target for HIRI.

In addition to regulating neutrophil activation and migration, targeting the inhibition of NETs formation and promoting their degradation is also an important direction for treating HIRI. The formation of NETs relies on neutrophil oxidative stress and the synergistic regulation of multiple molecular signaling pathways, making drug interventions targeting the NETosis process a potential therapeutic target for alleviating HIRI. Superoxide induces NET release through the TLR4/NOX pathway and the combination of allopurinol (superoxide inhibitor) and diphenyl iodinium (NOX inhibitor) can markedly suppress NET formation in mice and alleviate liver injury (117). Elevated serum IL-17 levels are directly associated with increased neutrophil infiltration and NET formation in the liver, suggesting that IL-17 is a potent NET inducer (118). Similarly, in the kidney IRI mouse model, infiltrated neutrophils were the main source of IL-17 production, further promoting neutrophil migration (119). Moreover, research by Lin et al (120) indicates that IL-17-positive neutrophils, abundant in human psoriatic lesions, can release IL-17 through the induction of NETs. Therefore, targeting IL-17 with neutralizing antibodies can reduce NET formation and mitigate IR-induced damage. Histone citrullinase PAD4 is a key mediator of NET formation and its inhibitors (YW3-56 and YW4-03) can markedly reduce liver injury in HIRI mice (40). Similar effects were observed in mouse models when targeting NE or using specific MPO inhibitors. Compared with wild-type animals, NE inhibitor-treated PAD4KO or wild-type animals showed markedly smaller tumors, reduced neutrophil infiltration and fewer NETs (121), suggesting that anti-PAD4 strategies may provide a new pathway for HIRI treatment. Yang et al (122) found that Aldh2 deficiency induced NOX2-dependent NETosis through the endoplasmic reticulum stress/GST2/LTC4 pathway and the LTC4 receptor antagonist montelukast might be a potential therapeutic option. Other studies have indicated that acrolein promotes NET formation by activating the NOX2/P38MAPK signaling pathway, delaying postoperative liver recovery (123). Targeting NOX2 and P38MAPK pathways can suppress NET generation in chronic liver disease patients but improve postoperative liver function (123). These strategies effectively block the source of NET formation and reduce liver tissue damage. However, excessive NET accumulation can still trigger localized inflammatory damage, making the promotion of NET degradation a key aspect of treatment. Under physiological conditions, serum deoxyribonuclease (DNase; e.g., DNase1) is the main nuclease responsible for degrading NETs (124,125). Liu et al (126) innovatively constructed a stroke-homing peptide (SHp) fused with DNase1 (SHp-DNase1), which enhances DNase stability and targets NETs in thromboembolism events. Combined with ceftriaxone sodium therapy, this approach synergistically controls inflammation and resolves NET-induced microcirculatory impairment. The validation of these multidimensional intervention strategies in the HIRI model provides an innovative direction for precisely regulating NET biology and overcoming the therapeutic bottleneck in HIRI treatment.

Neutrophils contribute to liver reperfusion injury through migration and release of inflammatory mediators and by generating ROS, which exacerbate tissue damage. Excess ROS can attack cell membrane lipids, mitochondrial structures and DNA, triggering oxidative stress, leading to hepatocyte apoptosis or necrosis, worsening inflammation and impairing liver function (127). Hence, targeting neutrophil-mediated oxidative stress has emerged as a key strategy for preventing and treating HIRI, with antioxidant therapies gaining increasing attention.

Antioxidants can effectively alleviate liver reperfusion injury by scavenging free radicals and reducing oxidative stress (127). In animal models, various antioxidants have shown protective effects, including N-acetylcysteine (NAC) (117), vitamin E, vitamin C (128). NAC, as a precursor for glutathione (GSH) synthesis, replenishes intracellular cysteine, promotes GSH production and enhances endogenous antioxidant capacity, thereby reducing ROS-induced liver damage (117). Vitamin E, a lipid-soluble antioxidant primarily localized in cell membranes, interrupts the chain reaction of lipid peroxidation. Vitamin C, a water-soluble antioxidant, directly neutralizes free radicals and regenerates vitamin E, synergistically exerting protective effects (128).

In recent years, nano-selenium (nano-Se) has gained popularity in antioxidant therapy due to its high efficiency and low toxicity. Selenium is a necessary cofactor for various antioxidant enzymes, such as glutathione peroxidase, superoxide dismutase and catalase and it helps regulate cellular redox balance. Nano-Se not only directly scavenges free radicals such as DPPH and ABTS but also enhances the activity of the endogenous antioxidant system (129). Nano-Se particles modified with chitosan of different molecular weights exhibit superior free radical scavenging capacity and concentration-dependent ROS inhibition in skin and intestinal cells, higher selenium concentrations yield stronger inhibitory effects (130). Compared with traditional selenium preparations, nano-Se has higher bioavailability and targeting potential. It exerts hepatoprotective effects through multiple mechanisms, including ROS clearance, enzyme activity enhancement and apoptosis inhibition, with lower toxicity, showing broad potential in preventing and treating HIRI (131).

However, single antioxidant therapy is insufficient to comprehensively control the complex pathological process of HIRI. Regarding the interplay between oxidative stress and inflammation, which forms a 'vicious cycle' (51), combined antioxidant and anti-inflammatory therapy strategies are considered more advantageous (132). On the one hand, antioxidants can alleviate oxidative stress and inhibit neutrophil activation and infiltration; on the other hand, anti-inflammatory drugs, such as non-steroidal anti-inflammatory drugs or corticosteroids, can effectively reduce local liver inflammation (133,134). Their synergistic effects hold promises for more efficiently mitigating liver tissue damage and promoting functional recovery (132).

Notably, following HIRI, the expression of polo-like kinase 2 was markedly upregulated, indicating its involvement in regulating the injury process. Biocompatible Prussian blue (PB) scavengers possess ROS-scavenging and anti-inflammatory properties (135) and may be used for HIRI treatment. PB scavengers are primarily distributed in the liver and have good alleviating effects on cell apoptosis, tissue damage and organ dysfunction following HIRI. In 2025, Shen et al (136) developed a PB nanzyme carrier system (met@PBN@Neu-CVs) based on neutrophil membrane coating for the delivery of metformin. This biomimetic nanoplatform utilizes the chemotactic properties of neutrophil membranes to actively target the inflamed liver, markedly enhancing drug accumulation in damaged tissues. This system can efficiently clear ROS, suppress inflammation and promote macrophage polarization toward the anti-inflammatory M2 phenotype. Consequently, it reduces HIRI-induced liver injury in a multidimensional manner, demonstrating strong therapeutic potential. The present review provided conceptual support for liver injury therapy; however, direct evidence regarding its role in HIRI still comes from animal models.

In conclusion, targeting neutrophil-driven oxidative stress and inflammation cascades, developing nano-antioxidant-based therapies combined with anti-inflammatory interventions, offers new approaches and effective methods for clinical prevention and treatment of liver reperfusion injury.

Nano-scale targeted drug delivery systems have shown broad application prospects in reducing IRI and promoting tissue function recovery. Biomimetic nanoparticles inherit the surface antigen profiles of their source cells and possess multiple biological functions, including precise targeted delivery, high accumulation in lesion sites and the ability to regulate the immune microenvironment (137). As key effector cells in inflammation, neutrophils play a central role in recognizing and responding to tissue damage. Their surface expresses various adhesion molecules, chemokine receptors and damage-associated molecular patterns, allowing them to migrate directionally and accumulate at inflammation sites (25). Based on this characteristic, neutrophil membrane-coated liposome delivery systems can effectively bind to local chemokines. For example, neutrophil membrane-coated liposome drug delivery systems effectively target and accumulate at rheumatoid arthritis lesion sites with joint-specific precision (138) and neutrophil membrane-wrapped therapeutic liposomes can target acute lung injury treatment (139).

Furthermore, in vitro and in vivo studies have shown that neutrophil-derived extracellular vesicles not only efficiently load therapeutic drugs but also specifically bind to damaged endothelial cells, markedly alleviating endothelial dysfunction and improving sepsis-induced lung injury. Yuan et al (140) developed a ROS-responsive neutrophil-derived vesicle system (SOD2-Fer-1@CVs), which could specifically accumulate in inflammation tissues with high oxidative stress, thus enabling the controlled release of superoxide dismutase 2 (SOD2) and ferroptosis inhibitor Fer-1 upon ROS stimulation. SOD2-Fer-1@CVs intervene in the core pathological processes of IRI from multiple dimensions: alleviating oxidative stress, adsorbing and neutralizing pro-inflammatory cytokines, inhibiting ferroptosis, restoring endothelial barrier integrity and promoting macrophage polarization to the anti-inflammatory M2 phenotype. Ultimately, it markedly alleviates IRI following lung transplantation, demonstrating strong multi-effect synergistic therapeutic potential.

At the same time, stem cell therapy, as an important direction in regenerative medicine, has shown great potential in various disease fields. In liver IRI, mesenchymal stem cells (MSCs) have garnered widespread attention due to their immune regulatory, anti-inflammatory and tissue repair functions. MSCs can secrete anti-inflammatory factors such as IL-10 and TGF-β, regulating neutrophil activation and reducing their infiltration in the liver, thereby inhibiting excessive inflammatory responses. Additionally, MSCs can promote hepatocyte proliferation and regeneration, alleviating liver failure caused by reperfusion. Notably, EVs secreted by MSCs, particularly exosomes, are gradually being regarded as a cell-free alternative to full-cell therapies and are entering the clinical translation stage for liver disease treatment. These nano-sized vesicles are rich in bioactive components such as microRNA, proteins, lipids and functional mitochondria and can modulate immune responses through intercellular communication mechanisms. Research has demonstrated that human umbilical cord-derived MSC-EVs (hUC-MSC-EVs) effectively inhibit the formation of neutrophil extracellular traps (NETs) in mouse models (141), thereby ameliorating HIRI. The mechanism involves hUC-MSC-EVs transferring functional mitochondria to liver neutrophils, triggering mitochondrial fusion processes, repairing damaged mitochondrial structure and function and subsequently inhibiting abnormal NET release. This 'mitochondrial rescue' strategy reveals a novel protective mechanism whereby MSC-EVs exert effects by modulating the neutrophil metabolic-immune axis.