Weidong Jia
Xin Wei- Department of Hand and Foot Surgery, Orthopedics Center, First Hospital of Jilin University, Changchun, China
Ischemia-reperfusion injury in flaps refers to a cascade of pathophysiological reactions that aggravate tissue damage or even cause necrosis. During the period of ischemia followed by restored blood reperfusion, a burst of reactive oxygen species is produced. The prevention of flap ischemia-reperfusion injury remains a critical and challenging focus in current research. Xanthine oxidase serves as a major source of reactive oxygen species during ischemia-reperfusion. Allopurinol and febuxostat, xanthine oxidase inhibitor, primarily exerts its protective effects by inhibiting the activity of xanthine oxidase and reducing reactive oxygen species generation, thereby suppressing oxidative stress damage. Additionally, it may improve flap survival through other mechanisms, such as modulating inflammatory responses and suppressing apoptosis. This article systematically reviews the pathological mechanisms and therapeutic advances of skin flap ischemia-reperfusion injury, with a focus on exploring the role of xanthine oxidase inhibitors in flap protection by targeting and regulating oxidative stress pathways, aiming to provide new therapeutic strategies and theoretical basis for clinical prevention and treatment of skin flap ischemia-reperfusion injury.
1 Introduction
Flap transplantation is a widely applied surgical technique for repairing skin, subcutaneous soft tissue, or deeper structures such as nerves, tendons, and bones damaged by trauma, tumors, or burns. It plays a critical role in restoring both appearance and function. However, ischemia–reperfusion (I/R) injury is a major contributor to flap failure. In a survey of 1,142 cases, the average survival rate of free flap transplantation exceeded 90%. Nevertheless, 82% of flaps experienced circulatory impairment within the first 24 h, and 9.9% required secondary revascularization. In a large follow-up study of 1,258 free flaps, Chiu et al. reported an 11.9% re-exploration rate, with 58% of cases showing vascular pedicle thrombosis. Of these, only ∼30% were successfully salvaged by thrombectomy and vascular re-anastomosis (Chiu et al., 2017). The lack of timely and effective monitoring and intervention—whether in free or pedicled flaps—remains a major limitation. Postoperative blood supply can be compromised by vasospasm, tissue edema-induced compression, pedicle torsion, or thrombosis. Even when revascularization is achieved, secondary I/R injury often undermines success (Dan Dunn et al., 2015), aggravating tissue damage or causing flap necrosis, with profound effects on prognosis and quality of life. Therefore, preventing and mitigating I/R injury is essential for improving flap survival, functional recovery, and overall patient outcomes.
1.1 Pathophysiological mechanisms of flap ischemia-reperfusion injury
Ischemia–reperfusion injury represents a cascade of pathological events involving metabolic dysfunction, cellular damage, and inflammation. During ischemia, oxygen and nutrient deprivation impair mitochondrial oxidative phosphorylation, causing a sharp decline in adenosine triphosphate (ATP) production. Cells switch to anaerobic glycolysis, leading to plenty of lactate accumulation and metabolic acidosis. Concurrent energy depletion disrupts Na+/K+ and Ca2+ pumps, promotes phospholipid degradation, and increases free radical generation. These processes cause cellular swelling, increased membrane permeability, loss of membrane integrity (Mittal et al., 2014), and leakage of intracellular contents (Wu et al., 2018). Additionally, ischemia reduces endothelial nitric oxide (NO) production while increasing vasoconstrictors such as endothelin, thereby inducing vasospasm (Dominguez et al., 2021).
After ischemia, reperfusion further exacerbates injury. Restoration of blood flow, combined with mitochondrial dysfunction and ionic imbalance, activates the xanthine oxidoreductase (XOR) system, producing large amounts of reactive oxygen species (ROS). This oxidative burst triggers mitochondrial injury, calcium overload, leukocyte infiltration, and inflammatory responses (Granger and Kvietys, 2015). ROS—including superoxide anion (O2−), hydroxyl radical (·OH), hydrogen peroxide (H2O2), lipid peroxyl radical (LOO·), peroxynitrite (ONOO−) and so on—are normally involved in physiological processes such as signal transduction, metabolism, and cell proliferation. However, excessive ROS drive oxidative stress, damaging lipids, proteins, and DNA. ROS also activate inflammatory pathways, promoting leukocyte recruitment and pro-inflammatory cytokine release (Kalogeris et al., 2012). The interplay of oxidative stress and inflammation ultimately results in cell death and tissue injury, contributing to multiple disease processes. Overview of the mechanism of ischemia-reperfusion injury and the subsequent transformation of superoxide anion is illustrated in Figure 1 (Choi et al., 2015).
Figure 1. Diagram illustrating cellular changes during ischemia and reperfusion. In ischemia, ion-exchange channel failure, anaerobic metabolism, reduced ATP, cell swelling, and pH drop occur. In reperfusion, calcium overload, mitochondrial swelling, and reactive oxygen species formation from pathways for the XOR system, NADPH oxidase system, and mitochondrial respiratory chain lead to lower antioxidants. The subsequent transformation of superoxide anion. ROS activate inflammation, and apoptosis, with markers expression like NLRP3 inflammasome, NF-κB, p38/JNK MAPK pathways, and proteins such as Bcl-2, Bax, and Bak.
1.2 Pathways of oxygen free radical production and following inflammatory responses and apoptosis and necrosis during intracellular ischemia–reperfusion
Among the major ROS sources described, the xanthine oxidoreductase system, the NADPH oxidase (Nox) family, and the mitochondrial respiratory chain are considered primary mediators of I/R-induced oxidative stress. These pathways represent priority therapeutic targets in organ and tissue I/R injury. While all three enzymatic systems are broadly expressed, the dominant ROS source likely varies among tissues (Wu et al., 2018). Following reperfusion, aforesaid ROS activate multiple inflammatory factors, including the NLRP3 inflammasome, NF-κB, and the p38/JNK MAPK pathways etc. Inflammatory mediators are released in large quantities, amplifying oxygen radical generation and inflammatory responses in a feed-forward cycle of tissue damage. Excessive ROS and inflammation further promote apoptosis and necrosis, exacerbating organ injury and, in severe cases, leading to widespread tissue necrosis (Jurc et al., 2022; Güler et al., 2023).
1.2.1 Xanthine oxidoreductase system
Xanthine oxidoreductase (XOR), a member of the molybdenum–iron–sulfur flavin hydroxylase family, is widely distributed across multiple organs, including the liver, intestine, lung, kidney, heart, brain, and plasma (Wu et al., 2018). XOR exists in two interconvertible forms: xanthine oxidase (XO) and xanthine dehydrogenase (XDH) (Wang et al., 2008). These enzymatic systems transfer electrons from xanthine to oxygen or NAD+, respectively, generating O2−, H2O2, and NADH (Berry and Hare, 2004). The hypothesis that XO is a major source of ROS in I/R injury was first proposed by Downey JM in 1990 to explain the increased vascular permeability observed after 1 hour of low-flow ischemia followed by reperfusion in the cat small intestine (Granger et al., 1981). XO-derived ROS appear within minutes of reperfusion, whereas neutrophil infiltration (activating the NADPH oxidase system) and mitochondrial dysfunction-mediated ROS generation typically require several hours (Harrison, 2002). Ono T et al. further demonstrated that superoxide generation markedly increased during the early phase of I/R and was significantly attenuated by allopurinol (Ono et al., 2009), confirming XO as the predominant source of ROS at reperfusion onset. This rapid ROS burst directly induces lipid peroxidation and activates neutrophils (via NADPH oxidase) and the complement system, establishing a vicious cycle of “oxidation–inflammation” (Granger, 2025). Accordingly, XOR inhibition disrupts the early ROS surge and prevents downstream tissue injury.
1.2.2 NADPH oxidase system
The Nox/Duox family of NADPH oxidases represents another important source of ROS in I/R (Lassègue and Griendling, 2010). These enzymes are widely expressed across cell types, including vascular cells, with significant mRNA and protein expression documented in multiple tissues. Nox/Duox enzymes are established contributors to ROS production under diverse pathological conditions. Their role in reperfusion injury is supported by two key observations (Chiu et al., 2017): upregulated expression and activity of Nox in ischemic tissues, and (Dan Dunn et al., 2015) attenuation of ROS generation and I/R-induced injury following pharmacological inhibition or genetic suppression of Nox expression (Yokota et al., 2011).
1.2.3 Mitochondrial oxidative respiratory chain
Mitochondria constitute a third major ROS source during I/R. Mitochondrial respiratory chain–derived ROS were first reported in 1966 (Jensen, 1966). Chance et al. subsequently demonstrated that isolated mitochondria could generate H2O2 (Chance et al., 1979), later shown to arise from superoxide dismutation within mitochondria (Forman and Kennedy, 1974). ROS production primarily occurs at Complex I (NADH dehydrogenase) and Complex III (ubiquinol–cytochrome c reductase) of the respiratory chain.
1.3 The influnce of endogenous antioxidant defense systems during ischemia–reperfusion injury
The body maintains a sophisticated antioxidant defence system that relies on endogenous enzymatic and nonenzymatic antioxidants. The role of the main defense antioxidants which basically include superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) is important and indispensable to resist damaging effects from relevant reactive oxidative substance in the entire defense strategy of antioxidants, especially in reference to super oxide anion radical (O2−) which is continuously produced during normal metabolic processes (Ighodaro and Akinloye, 2018; Jomova et al., 2024).
2 Mechanism and therapeutic advances of xanthine oxidase inhibitors in flap ischemia-reperfusion injury
2.1 Pharmacological effects of xanthine oxidase inhibitors
Currently, the clinically available XO inhibitors include allopurinol and febuxostat.
Allopurinol, metabolized in vivo to oxypurinol, competitively inhibits XO, blocking the conversion of hypoxanthine and xanthine to uric acid. Febuxostat, in contrast, binds directly to the molybdenum pterin center at the XO active site, suppressing enzymatic activity and simultaneously reducing both uric acid and ROS production. Both agents are approved for treating acute and chronic hyperuricemia and related disorders (Nishino and Okamoto, 2015). Beyond urate lowering, they exert protective effects in various models of I/R injury (Ullah et al., 2020; Sun Guifang, 2019; Yajuan, 2019; Zhang et al., 2021; Shin et al., 2015; Wang et al., 2015; Tsuda et al., 2012). Allopurinol not only suppresses ROS production and dampens inflammation but also facilitates ATP regeneration through the purine salvage pathway by sparing hypoxanthine, thereby ameliorating energy metabolism disturbances (Frenguelli, 2019). Febuxostat, approved in 2009, has shown promising protective efficacy in animal I/R models. However, large-scale clinical evidence—particularly regarding long-term, multi-organ outcomes—remains limited. Moreover, concerns regarding elevated cardiovascular risk necessitate cautious use, especially in elderly patients and those with multiple comorbidities (Bruce, 2006). Notably, XO inhibitors act primarily at the extracellular surface of vascular endothelial cells, where XO is concentrated, making them more accessible via the bloodstream.
2.2 Therapeutic applications and advances of xanthine oxidase inhibitors in flap ischemia-reperfusion injury
2.2.1 Reduction of ROS generation and attenuation of oxidative stress
The functional dynamics of the xanthine oxidoreductase (XOR) system are illustrated in Figure 2. Under physiological conditions, hypoxanthine is oxidized by xanthine dehydrogenase (XDH) in the presence of H2O and NAD+, producing xanthine, NADH, and H+. XDH further catalyzes the conversion of xanthine to uric acid, again generating NADH and H+. This pathway does not directly generate reactive oxygen species (ROS), as electrons are efficiently transferred to NAD+. Reactive oxygen species (ROS) are catalyzed by superoxide dismutase (SOD) to form hydrogen peroxide, which is subsequently decomposed into non-toxic water and oxygen by catalase (Ighodaro and Akinloye, 2018). During ischemia–reperfusion (I/R), however, ATP degradation in the ischemic phase leads to marked accumulation of hypoxanthine. Concurrently, intracellular Ca2+ overload activates Ca2+-dependent proteases that convert XDH to xanthine oxidase (XO) through oxidation of critical cysteine residues and/or limited proteolysis. Upon reperfusion, when oxygen supply is restored, XO utilizes molecular oxygen as the terminal electron acceptor to catalyze hypoxanthine and xanthine oxidation into uric acid. Moreover, suppression or impairment of the antioxidant system, along with excessive generation of ROS, results in substantial depletion of antioxidant enzymes such as SOD, CAT, and GPX. Consequently, released large amounts of O2− and H2O2 further gives rise to more toxic reactive species, including ·OH, LOO· and ONOO− (Ighodaro and Akinloye, 2018). The resulting ROS directly oxidize amino acid residues, induce conformational alterations, and promote protein cross-linking, thereby impairing enzymatic function. They can also damage nucleic acids by oxidizing bases, breaking the deoxyribose backbone, or disrupting base-pairing, which interferes with replication and transcription. Furthermore, ROS accelerate telomere attrition and drive cellular senescence (Cecarini et al., 2007).
Figure 2. Metabolic pathway diagram showing the conversion of ATP and GTP with xanthine dehydrogenase (XDH) or xanthine oxidase (XO) into uric acid via intermediates like hypoxanthine and xanthine and mechanisms of action of XO inhibitors.
Cytokines including interleukin-1 (IL-1), interferon-γ (IFN-γ), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) (Dopp et al., 2011; Schwartz et al., 1995) exacerbate this process by upregulating XDH/XO mRNA expression, enhancing XOR activity (Mittal et al., 2014; Dopp et al., 2011; Schwartz et al., 1995; Falciani et al., 1992; Poss et al., 1996; Pfeffer et al., 1994), and promoting the XDH-to-XO shift (Falciani et al., 1992; Vorbach et al., 2003). The activated XOR system, in turn, drives massive ROS release and further cytokine production (Berry and Hare, 2004; Xiaotao et al., 2024; Yapca et al., 2013).
Experimental studies support the protective role of XO inhibition in flap survival. Prada FS et al. reported that allopurinol increased the survival area of rat inferior epigastric artery perforator flaps (Prada et al., 2002), while Mehdi Rasti Ardakani et al. demonstrated reduced necrosis in abdominal flaps in dogs following allopurinol treatment (Ardakani, 2017). Collectively, these findings suggest a beneficial effect of allopurinol in improving flap viability.
Mechanistically, Guansong Wang et al. showed that hypoxia activates XDH/XO via the IL-6–JAK/STAT pathway in pulmonary vascular endothelial cells (Wang et al., 2008). Allopurinol, as an XO inhibitor, suppresses IL-6 expression (Prieto-Moure et al., 2017; Gitaswari et al., 2024), thereby dampening IL-6–JAK/STAT–mediated XO activation, reducing ROS production (Wang et al., 2008), and attenuating inflammatory signaling.
In addition, Zhang Y.S. et al. identified the XO–VPO1 axis as a novel oxidative stress pathway involving XO and vascular peroxidase 1 (VPO1), a heme-containing peroxidase. Activation of this pathway drives excessive ROS production, including hypochlorous acid (HOCl), H2O2, and O2−, thereby exacerbating cellular damage. Allopurinol inhibits this axis by reducing XO activity, suppressing XO-derived H2O2 and uric acid, and downregulating VPO1 expression at both the mRNA and protein levels (Zhang et al., 2021). Moreover, allopurinol upregulates endogenous antioxidant defenses, such as glutathione and catalase (Sagor et al., 2015; Milcheski et al., 2013). Superoxide (O2−) generated during I/R also reacts rapidly with nitric oxide (NO), a critical vasoprotective molecule that maintains vasodilation, suppresses smooth muscle proliferation, limits platelet aggregation, and prevents leukocyte adhesion. This reaction yields peroxynitrite (ONOO−), depleting NO bioavailability, impairing vasodilation, and inducing endothelial dysfunction. Oxypurinol, the active metabolite of allopurinol, has been shown to counteract this effect (Cardillo et al., 1997).
Further evidence from Gitaswari I’s group indicates that during flap I/R, allopurinol reduces ROS by inhibiting XO, suppresses NF-κB activation, downregulates pro-inflammatory cytokines (IL-6, TNF-α), and upregulates vascular endothelial growth factor (VEGF) (Gitaswari et al., 2024). Increased VEGF expression enhances NO and endothelin release (Yi et al., 2020), thereby promoting angiogenesis, vasodilation, and microcirculatory recovery. Collectively, these effects significantly improve flap survival (Gitaswari et al., 2024).
Kang HB et al. reported that oxypurinol, the active metabolite of allopurinol, induces the expression of heme oxygenase-1 (HO-1) (Kang et al., 2023). HO-1 catalyzes the degradation of cytotoxic free heme in the presence of O2 and NADPH oxidase, producing biliverdin, Fe2+, and carbon monoxide (CO). Biliverdin is subsequently converted to bilirubin, which exerts potent antioxidant effects by neutralizing reactive oxygen species (ROS) (Huang et al., 2022; Chen et al., 2020). Simultaneously, reduced NADPH oxidase activity limits O2− production, promotes Fe2+ sequestration by ferritin, and suppresses the Fenton reaction (Fujii et al., 2010; Oh et al., 2013). CO mediates additional protective effects: it inhibits NF-κB nuclear translocation, thereby reducing pro-inflammatory cytokines (TNF-α, IL-6) and adhesion molecules (ICAM-1, VCAM-1), which collectively limit leukocyte infiltration (Araujo et al., 2012). Moreover, CO activates the soluble guanylate cyclase–cGMP pathway, enhancing vasodilation and improving tissue perfusion (Chen et al., 2015; Vera et al., 2005). Bilirubin also inhibits activation of the NLRP3 inflammasome, further curbing inflammation (Zhang et al., 2025; Li et al., 2022; Vítek, 2020).
Soliman E et al. demonstrated that allopurinol mitigates ischemia–reperfusion (I/R) injury by modulating the xanthine oxidase (XO)–peroxisome proliferator-activated receptor γ (PPAR-γ) signaling pathway (Soliman et al., 2023). PPAR-γ regulates oxidative stress by suppressing pro-oxidant genes such as NADPH oxidase (Soliman et al., 2023) and preserving mitochondrial structure and function (Yeligar et al., 2018), thereby reducing ROS generation. This lowers NO oxidation into peroxynitrite (ONOO−) and concurrently enhances antioxidant enzyme expression, including superoxide dismutase and glutathione peroxidase (De Nuccio et al., 2020; Yongyue and Yingjing, 2020). PPAR-γ activation also inhibits NF-κB signaling and downregulates transcription of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) (Bernardo and Minghetti, 2006). In addition, it promotes cell survival by upregulating anti-apoptotic proteins (Bcl-2) and suppressing pro-apoptotic proteins (Bax) (Wu et al., 2021; Wang et al., 2023). Mechanistically, allopurinol inhibits XO, reduces ROS production, and upregulates PPAR-γ, creating a feedback loop that attenuates oxidative stress and inflammation, ultimately protecting tissues and organs.
2.2.2 Inhibition of inflammatory response
During I/R, ROS activate multiple inflammatory cascades, including the NLRP3 inflammasome, NF-κB, and the p38/JNK MAPK pathways. Terada et al. observed that neutrophils exacerbate endothelial injury through the release of reactive oxygen metabolites (O2−, H2O2, HOCl), whereas allopurinol suppresses neutrophil adhesion to endothelial cells (Granger and Kvietys, 2015; Ichikawa et al., 1997). Beyond direct ROS inhibition, allopurinol reduces XO-dependent signaling, thereby indirectly blocking NF-κB activation (Guzik et al., 2025). This significantly downregulates transcription of IL-6, IL-1β, and TNF-α (Choi et al., 2015; Shin et al., 2015; Gitaswari et al., 2024; Shenkar and Abraham, 1997; Bahriz et al., 2025). Excessive activation of the IL-6–JAK/STAT3 axis further promotes apoptosis and endothelial barrier dysfunction; allopurinol alleviates this by lowering IL-6 expression and STAT3 phosphorylation (Prieto-Moure et al., 2017). Likewise, I/R-induced activation of the JNK/p38 MAPK pathway, which drives inflammatory mediator release and stress responses, is effectively suppressed by allopurinol (Shin et al., 2015; Kang et al., 2023; Kuanlu and Yong, 2010).
Zhou J. Qiao et al. showed that ROS accumulation during I/R induces cellular damage and promotes the release of high-mobility group box 1 (HMGB1). HMGB1 activates the TLR4/NF-κB pathway, driving TNF-α and IL-6 release, upregulating pro-apoptotic proteins (Bax, Caspase-3), and downregulating the anti-apoptotic protein Bcl-2. Allopurinol reduces ROS generation, thereby suppressing HMGB1 activity, alleviating inflammation and apoptosis, and ultimately mitigating organ injury (Zhou et al., 2016). Similarly, Ives A. et al. demonstrated that XO promotes mitochondrial ROS production via the PI3K–AKT–mTOR pathway, which activates the NLRP3 inflammasome. Allopurinol, as an XO inhibitor, markedly suppresses IL-1β secretion, thereby limiting inflammasome assembly and dampening the inflammatory response (Ives et al., 2015).
2.2.3 Anti-apoptotic effects
Apoptosis induced by oxidative stress occurs through multiple mechanisms, including mitochondrial dysfunction, activation of intracellular signaling pathways, and DNA damage. During reperfusion, the sudden influx of oxygen causes excessive production of reactive oxygen species (ROS) and intracellular Ca2+ overload, leading to the opening of the mitochondrial permeability transition pore (mPTP). This event results in mitochondrial membrane depolarization, matrix swelling, and outer membrane rupture, allowing pro-apoptotic factors such as cytochrome c to escape into the cytoplasm, thereby activating downstream apoptotic cascades. Membrane depolarization also contributes to ATP depletion, further promoting cell death (Choi et al., 2015; Pizzino et al., 2017; Wang et al., 2011). Recent studies confirm that ROS can induce mPTP opening during reperfusion, precipitating apoptosis (Lee and Lee, 2006). Allopurinol mitigates this process by reducing ROS generation, indirectly stabilizing the mitochondrial membrane, preserving ATP synthesis, and decreasing the release of pro-apoptotic factors through the mPTP, thus suppressing downstream apoptotic signaling (Choi et al., 2015; Brandão et al., 2018).
Among the major signaling pathways activated by oxidative stress, the p53 pathway plays a central role by upregulating pro-apoptotic proteins such as Bax and downregulating anti-apoptotic proteins such as Bcl-2 (Shin et al., 2015). Wang S. et al. demonstrated that febuxostat enhances the expression of anti-apoptotic proteins Bcl-2 and Bcl-XL, reduces pro-apoptotic proteins Bax and Bak, and increases the Bcl-2/Bax ratio (Wang et al., 2015). Other pathways implicated in oxidative stress-induced apoptosis include JNK and ERK. Ju-Hyun Shin et al. reported that during ischemia–reperfusion (I/R), pro-apoptotic signals such as JNK and p38 are upregulated and phosphorylated, whereas survival signals such as ERK are suppressed. Allopurinol reversed this pattern by markedly inhibiting JNK and p38 activation, attenuating the JNK-mediated suppression of Bcl-2, and increasing both the expression and phosphorylation of Bcl-2. In addition, allopurinol reduced Bax expression, thereby restoring the Bcl-2/Bax balance (Shin et al., 2015).
Oxidative stress also induces DNA damage, activating DNA damage response pathways and triggering apoptosis (Schumacker, 2006; Lin and Beal, 2006). ROS-mediated DNA damage promotes the formation of necrotic bodies via poly (ADP-ribose) polymerase (PARP) activation. Excessive PARP-1 activity depletes ATP stores and drives necrotic cell death (Ryu et al., 2010).
3 Discussion
Current evidence indicates that the enzymatic reactions underlying ischemia–reperfusion injury mediated by the xanthine oxidoreductase (XOR) system involve only xanthine oxidase (XO) and xanthine dehydrogenase. In the renal ischemia/reperfusion (I/R) model, both the XOR inhibitor (Soliman et al., 2023) and the knockout of the XOR gene in mice (Haga et al., 2017) significantly attenuate oxidative stress and inflammation, thereby improving renal function. In the cardiac I/R model, XO inhibitors suppress ROS production, preserve catalase activity, and mitigate myocardial injury (Brown et al., 1988). In the skeletal muscle I/R model, inhibition of the XOR system effectively alleviates oxidative stress in skeletal muscle (Kuroda et al., 2020; Paradis et al., 2016). Similarly, in the hepatic I/R model, XOR inhibitors reduce ROS generation by preventing xanthine accumulation during ischemia, eliminating free radicals. (Tang et al., 2022; Cannistrà et al., 2016; Singh et al., 2023). Collectively, evidence about organ I/R models highlight the pivotal role of the XO system in the burst of oxidative stress and comprehensively demonstrate the therapeutic potential of XO inhibitors, such as allopurinol, in preclinical I/R injury studies. In contemporary clinical research, XO inhibitors have shown promising efficacy in attenuating oxidative stress during I/R across multiple organs, including the heart, kidneys, and brain. Clinical trials in improving thrombolysis in myocardial infarction flow grades among patients with acute ST-segment elevation myocardial infarction following percutaneous coronary intervention (KermaniAlghoraishi et al., 2023), assessing long-term neurodevelopmental outcomes of neonates with hypoxic-ischemic encephalopathy (Maiwald et al., 2019) and in preventing contrast-induced nephropathy among patients undergoing percutaneous coronary intervention (Mansoor et al., 2021; Sarhan et al., 2023), substantial evidence indicates that xanthine oxidase inhibitors effectively have a positive impact. However, clinical evidence in flap I/R models remains lacking. Furthermore, investigating combination strategies that pair XO inhibition with other therapeutic modalities may offer synergistic protection for tissues and organs. Potential synergistic strategies include physical interventions (e.g., shockwave therapy, transcutaneous electrical stimulation) and pharmacological approaches, such as antioxidants (Chaves et al., 2020) (e.g., N-acetylcysteine, vitamin C),NADPH oxidase inhibitors (e.g., GKT137831) and mitochondria-protective agents (Ross and Benjamin, 2025) (e.g., SS-31/elamipretide). Such combination therapies may simultaneously suppress ROS generation at its source through XO inhibition while attenuating secondary mitochondrial ROS amplification. The NADPH oxidase system and the mitochondrial respiratory chain participate in I/R-related redox reactions through more complex mechanisms, with limited effective drug options and unresolved safety concerns. Additionally, experimental data suggest that Nox4 deficiency may aggravate oxidative stress injury (Schröder et al., 2012; Nlandu-Khodo et al., 2016), whereas allopurinol does not interfere with the protective Nox4–Nrf2 signaling axis. Moreover, integrating XO inhibitors with immuno-inflammatory-targeted therapies (e.g., NLRP3 or IL-1 inhibitors) may provide more comprehensive protection by suppressing both oxidative stress and downstream inflammatory cascades, thereby reducing reperfusion injury and delayed inflammatory necrosis more effectively (Zhang et al., 2024).
Taken together, XOR represents the earliest and most accessible source of ROS in I/R, offering a precise, clinically feasible, and safe therapeutic target. Inhibiting XOR disrupts the initial oxidative burst, reduces the release of inflammatory mediators while modulating autophagy and apoptosis and interrupts the subsequent “oxidation–inflammation–apoptosis” cascade. As the only antioxidant target consistently shown to be effective across multiple organ systems, XOR inhibition holds considerable promise for clinical translation. This review highlights the therapeutic relevance of XOR and its inhibitors in flap ischemia–reperfusion injury.
Author contributions
WJ: Writing – original draft, Writing – review and editing. XW: Writing – review and editing. XG: Writing – review and editing.
Funding
The authors declare that no financial support was received for the research and/or publication of this article.
Acknowledgements
Figures 1, 2 were created with a licensed version of BioRender.com.
Conflict of interest
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Keywords: ischemia-reperfusion injury, xanthine oxidase, flap, allopurinol, reactive oxygen species
Citation: Jia W, Wei X and Gong X (2025) Mechanism of xanthine oxidase in flap ischemia-reperfusion injury and advances in targeted therapy: a mini review. Front. Physiol. 16:1705704. doi: 10.3389/fphys.2025.1705704
Received: 15 September 2025; Accepted: 11 November 2025;
Published: 24 November 2025.
Edited by:
Dupiao Zhang, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, ChinaReviewed by:
Túlio de Almeida Hermes, Federal University of Alfenas, BrazilCopyright © 2025 Jia, Wei and Gong. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Xu Gong, Z29uZ3h1QGpsdS5lZHUuY24=