Lipoxin A4 improves myocardial ischemia/reperfusion injury through the Notch1-Nrf2 signaling pathway

Xueyun Yan; Anbang Chen; Yuanqi Gong; Jun Xu; Jinyue Lu; Linjuan Wang; Yunfei Fan; Naijing Gao; Le Zhou; Huaming Cao; Xiaodong Kuang

doi:10.1515/biol-2025-1200

Article Open Access

Lipoxin A4 improves myocardial ischemia/reperfusion injury through the Notch1-Nrf2 signaling pathway

Xueyun Yan , Anbang Chen , Yuanqi Gong , Jun Xu , Jinyue Lu , Linjuan Wang , Yunfei Fan , Naijing Gao , Le Zhou , Huaming Cao and Xiaodong Kuang

Published/Copyright: November 20, 2025

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From the journal Open Life Sciences Volume 20 Issue 1

Abstract

This study investigates the mechanism by which lipoxin A4 (LXA4) attenuates myocardial ischemia/reperfusion injury (MIRI). Using a rat MIRI model, we evaluated coronary flow, histopathology, cardiac enzymes (cTnI/CK-MB), oxidative stress markers (superoxide dismutase, SOD; malondialdehyde, MDA; glutathione peroxidase, GSH-Px), and protein expression (neurogenic locus notch homolog protein 1 [Notch1], hairy and enhancer of split 1 [Hes1], nuclear factor-erythroid 2-related factor 2 [Nrf2], β-tubulin). Pharmacological inhibitors N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycinet-butylester (DAPT; Notch1) and ML385 (Nrf2) were co-administered with LXA4. Results demonstrated that I/R injury significantly increased microtubule disruption (48.5 ± 6.7% vs control 4.8 ± 0.9%; p < 0.01), decreased SOD (42.1 ± 5.3 vs 89.6 ± 8.7 U/mg), and GSH-Px (15.2 ± 2.1 vs 34.8 ± 4.5 U/mg), and elevated MDA (6.9 ± 0.8 vs 2.1 ± 0.3 nmol/mg; p < 0.05). Notch1, Hes1, and nuclear Nrf2 decreased by 58, 63, and 52%, respectively. LXA4 treatment reversed these effects (23.6 ± 3.6% microtubule disruption; p < 0.05), with DAPT or ML385 abolishing LXA4’s protection. These findings indicate that LXA4 protects against MIRI by preserving microtubule integrity and activating the Notch1/Hes1/Nrf2 pathway, revealing a novel mechanism for oxidative stress suppression in cardiomyocytes.

Graphical abstract

Keywords: oxidative stress; ischemia/reperfusion; LXA4; microtubules; Notch1-Nrf2.

1 Introduction

Myocardial ischemia/reperfusion injury (MIRI) represents a critical clinical paradox wherein reperfusion therapy-designed to salvage ischemic myocardium-paradoxically exacerbates tissue damage, leading to arrhythmias, ultrastructural collapse, and cardiomyocyte death [1,2]. This phenomenon arises from a self-perpetuating cascade of inflammatory activation, oxidative stress, and metabolic derangement. Inflammatory cytokines trigger neutrophil infiltration, amplifying injury through protease release and reactive oxygen species (ROS) overproduction [3,4], while mitochondrial dysfunction and calcium overload disrupt energy homeostasis, synergistically activating apoptotic and necroptotic pathways [4,5]. Despite decades of research, current therapies remain palliative, underscoring an urgent need for interventions targeting the root mechanisms of MIRI.

Lipoxin A4 (LXA4), an endogenous pro-resolving mediator, has emerged as a promising candidate for mitigating ischemia/reperfusion (I/R) injury due to its dual capacity to suppress inflammation and enhance tissue repair [6,7,8]. Preclinical studies demonstrate its efficacy in reducing infarct size and improving cardiac function across multiple organ systems [9,10,11]. However, existing research is yet to fully delineate how LXA4 preserves cardiomyocyte ultrastructure, particularly its role in stabilizing microtubule networks essential for mechanical and signaling integrity. Furthermore, while LXA4 is known to modulate oxidative stress, the interplay between its antioxidant effects and redox-sensitive signaling pathways – such as the neurogenic locus notch homolog protein 1 (Notch1)/nuclear factor-erythroid 2-related factor 2 (Nrf2) axis, a central regulator of cellular stress adaptation – remains poorly characterized. These knowledge gaps limit the translation of LXA4’s therapeutic potential into clinically actionable strategies. The Notch1-Nrf2 signaling crosstalk enhances cardiomyocyte viability and antioxidant capacity by activating the Keap1-Nrf2 pathway to suppress mitochondrial ROS generation and improve mitochondrial function, representing a promising therapeutic strategy against myocardial I/R injury [12,13]. However, the specific role and interplay of the Notch1-Nrf2 axis in MIRI, particularly in the context of LXA4 intervention, remain largely unexplored.

This study addresses these limitations by systematically interrogating LXA4’s cardioprotective actions through an integrated framework. First, we explore its ability to maintain microtubule stability, a structural determinant of cardiomyocyte resilience often compromised during I/R injury. Second, we dissect its role in rebalancing oxidative stress by restoring antioxidant enzyme activity (e.g., superoxide dismutase [SOD], glutathione peroxidase [GSH-Px]) and suppressing lipid peroxidation markers (e.g., malondialdehyde [MDA]). Crucially, we unravel the mechanistic link between LXA4 and the Notch1/Nrf2 pathway, demonstrating how this mediator activates Nrf2-driven antioxidant defenses while modulating Notch1-dependent cellular stress responses. By unifying structural, biochemical, and molecular analyses, our work reveals that LXA4 disrupts the vicious cycle of MIRI not through isolated mechanisms, but via coordinated preservation of cellular architecture, redox homeostasis, and stress-adaptive signaling.

Our findings provide the first evidence that LXA4’s cardio protection is mechanistically rooted in its capacity to stabilize microtubule networks and activate the Notch1/Nrf2 axis, offering a dual-target strategy against MIRI. This integrated approach contrasts with conventional therapies that address singular pathological pathways, positioning LXA4 as a multifaceted therapeutic agent. By resolving longstanding uncertainties about its mode of action, this study bridges critical gaps between preclinical promise and clinical application, paving the way for targeted interventions that mitigate reperfusion injury while promoting myocardial recovery.

2 Materials and method

2.1 Animal models and experimental design

Male Sprague-Dawley rats (8 weeks old, 200–250 g) were obtained from Changsha Tianqin Biotechnology Co., Ltd (China) and maintained under specific pathogen-free conditions at 25 ± 1°C with a 12 h light/dark cycle. Animals were fed irradiated sterile feed and provided ad libitum access to water.

Ethical approval: The research related to animal use has been complied with all the relevant national regulations and institutional policies for the care and use of animals, and has been approved by the Animal Ethics Committee of Nanchang University (Approval NO. NCULAE-20220624013).

2.2 Drug administration and experimental groups

To determine the optimal therapeutic dose of LXA4 (Ann Arbor, MI, USA), a total of 60 rats were randomly assigned to 5 groups (n = 12, per group): a control group (sham surgery), I/R group, and three I/R groups receiving intraperitoneal injections of LXA4 at 100, 200, or 400 μg/kg. A subsequent cohort of 72 rats was utilized and expanded to 6 groups (n = 12, per group): a subsequent experiment expanded the cohort to 6 groups: control, LXA4 alone (optimal dose), I/R, I/R+LXA4, I/R+LXA4+DAPT (Notch1 inhibitor, 100 μg/kg; Sigma-Aldrich, Germany), and I/R+LXA4+ML385 (Nrf2 inhibitor, 100 μg/kg; Sigma-Aldrich, USA). The doses of N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycinet-butylester (DAPT) (100 μg/kg) and N-[4-[2,3-Dihydro-1-(2-methylbenzoyl)-1H-indol-5-yl]-5-methyl-2-thiazolyl]-1,3-benzodioxole-5-acetamide (ML385) (100 μg/kg) were selected based on previous studies demonstrating their efficacy in effectively inhibiting the respective target pathways in rodent models of cardiovascular injury without inducing significant off-target toxicity [14,15]. LXA4 and inhibitors were dissolved in dimethyl sulfoxide (DMSO; Solarbio, China) and diluted in saline to ensure a final DMSO concentration <0.1%. All agents were administered intraperitoneally 10–30 min prior to ischemia induction.

2.3 Surgical induction of MIRI

MIRI was established as previously described [16,17]. Briefly, rats were anesthetized via intraperitoneal injection of pentobarbital sodium (40 mg/kg) followed by continuous 1.5–2% isoflurane via facemask. Anesthetic depth was confirmed by loss of pedal withdrawal reflex (toe pinch), abolished corneal reflex, and stable respiratory rate (50–70 bpm), with core temperature maintained at 37.0 ± 0.5°C using a heating pad. Following heparinization (300 IU, i.p.), a left thoracotomy was performed to expose the heart. The left anterior descending coronary artery was ligated 2 mm below the left auricle for 30 min to induce ischemia. Hearts were then rapidly excised, immersed in ice-cold Krebs–Henseleit (K-H) buffer, and mounted on a Langendorff perfusion system for retrograde perfusion with oxygenated K-H buffer (95% O₂/5% CO₂, pH 7.35–7.45) at 37°C and constant pressure (75 mmHg). The ex vivo Langendorff model was selected to isolate cardiac-specific mechanisms without confounding systemic factors, allowing precise control over perfusion conditions and drug delivery.

2.4 Perfusion protocols and tissue collection

Control hearts underwent continuous perfusion with K-H buffer for 120 min without ischemia. In the I/R group, 30 min of global ischemia preceded 120 min of reperfusion. For intervention groups, LXA4 and/or inhibitors were administered prior to ischemia, followed by identical perfusion protocols. After reperfusion, left ventricular tissue was either immediately frozen in liquid nitrogen for molecular analyses or embedded in optimal cutting temperature (OCT) compound for cryosectioning. After experimental procedures, euthanasia was performed under deep anesthesia by intracardiac injection of potassium chloride (1 M, 0.5 mL/kg) with prior heparinization (300 IU, i.p.), followed by bilateral thoracotomy to confirm death. This protocol adheres to AVMA Guidelines (2020) for rodents >200 g. Transverse sections were stored at −80°C for subsequent immunofluorescence staining of microtubules, while remaining tissue was reserved for biochemical assays and Western blot analysis.

2.5 Assessment of coronary blood flow dynamics

Coronary blood flow was quantitatively evaluated before and after I/R by measuring perfusate effluent from the right atrium. Perfusate volume was collected into graduated cylinders over timed intervals, with coronary flow rate calculated as mL/min/g heart weight. Coronary artery blood flow velocity was simultaneously monitored using a calibrated flowmeter, and data were excluded if baseline flow rates fell below 10 mL/min to ensure physiological relevance. Following reperfusion, left ventricular tissue was immediately dissected into two portions: one fixed in 4% paraformaldehyde for histopathological evaluation, and the remaining was snap-frozen in liquid nitrogen for subsequent molecular analyses. All samples were stored at −80°C until processing to preserve biochemical integrity. All assessments were performed in the ex vivo setup; no in vivo blood flow measurements were conducted. Perfusate effluent was collected over 1 min intervals at baseline, immediately post-ischemia, and at 30 min intervals during reperfusion.

2.6 Histopathological evaluation of myocardial tissue

Left ventricular tissues harvested post-reperfusion were fixed in 4% paraformaldehyde for 24 h, followed by sequential dehydration through an ethanol gradient, xylene clearing, and paraffin embedding. Serial Section (4–5 µm thickness) were prepared using a Leica RM2135 microtome (Leica Microsystems, Germany) and stained with hematoxylin and eosin (H&E) for light microscopic analysis (Olympus BX51, Japan). Histopathological alterations, including cardiomyocyte alignment, nuclear integrity, cytoplasmic swelling, and necrosis patterns, were systematically evaluated by blinded observers.

Myocardial injury severity was graded on a standardized 0–4 scale [18,19]: Grade 0 denoted intact tissue architecture with orderly cardiomyocyte arrangement, distinct striations, and absence of pathological changes; Grade 1 indicated focal subendocardial coagulative necrosis without transmural involvement; Grade 2 represented patchy necrosis spanning partial myocardial layers but lacking interlesional connectivity; Grade 3 exhibited confluent necrotic regions with interconnected lesions; Grade 4 corresponded to pan-myocardial necrosis involving the entire ventricular wall, often accompanied by mural thrombus formation. Quantitative analysis incorporated three randomized fields per section to ensure representative sampling.

2.7 Enzyme-linked immunosorbent assay (ELISA)

When myocardial injury occurs, troponin I (cTnI) and creatine kinase isoenzyme (CK-MB) are released into the coronary effluent. At the end of the reperfusion period, samples of the coronary effluent were obtained, and the levels of cTnI and CK-MB were evaluated using ELISA kits, following the instructions provided by the manufacturer (Solarbio, Beijing, China). Additionally, some myocardial tissue was homogenized into a 10% (w/v) solution, and the levels of superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) were evaluated with ELISA kits from the same supplier (Solarbio, Beijing, China).

2.8 Western blotting analysis

The tissue from the myocardium was subjected to homogenization through the use of a mechanical homogenizer, and RIPA lysis buffer (Beyotime, Jiangsu, China) was utilized to obtain the total protein content. The quantification of proteins was performed using the BCA Protein Assay Kit (Beyotime, Jiangsu, China). Subsequently, polyacrylamide gel electrophoresis (PAGE) was conducted, and subsequent to this, the samples were transferred to membranes made of polyvinylidene fluoride membranes (Millipore, Eschborn, Germany). A 5% w/v BSA solution was added to phosphate-buffered saline (PBS) containing 0.1% Tween 20 and sealed at ordinary temperatures for 1 h. Primary antibodies, including β-tubulin and β-actin from Santa Cruz Biotechnology (Santa Cruz, CA, USA), and Anti-Notch1, hairy and enhancer of split 1 (Hes1), and Nrf2 antibodies from Abcam (Cambridge, MA, USA), were diluted and added according to the instructions. Suitable secondary antibodies were diluted (1:1,000–1:2,000 v/v) in PBS with 0.1% Tween 20 at ordinary temperatures and incubated for 1 h. Signal detection was performed using the ECL reagent kit (Thermo Scientific Pierce, Rockford, IL, USA).

2.9 Assessment of microtubule structural integrity

To evaluate microtubule damage, myocardial tissues were perfused with periodate-lysine-paraformaldehyde fixative immediately following reperfusion, as described in established protocols [20,21]. Left ventricular specimens were excised, rinsed in ice-cold PBS (pH 7.4), and embedded in OCT compound for cryosectioning. Serial frozen sections (10 μm thickness) were incubated overnight at 4°C with a monoclonal anti-β-tubulin primary antibody, followed by a 1 h incubation with fluorescein isothiocyanate-conjugated goat anti-mouse secondary antibody (1:300 dilution; Abcam, Cambridge, MA, USA). After three washes with Tris-buffered saline containing 0.1% Tween-20, sections were mounted with antifade medium and imaged under a fluorescence microscope (BX51; Olympus, Tokyo, Japan) using standardized exposure parameters to ensure comparability across samples.

2.10 Quantitative analysis of microtubule disruption

Microtubule structural integrity was quantified using a validated scoring protocol¹⁸. For each specimen, 20–40 high-power fields (400× magnification) were randomly selected from 10 serial sections, with a focus on regions exhibiting diminished or absent β-tubulin fluorescence. Cross-sectional orientations were systematically excluded to standardize planar analysis. Digital images were spatially calibrated to a uniform scale (18 cm × 12 cm), and individual cardiomyocytes spaced at least 1 cm apart were demarcated as regions of interest. Areas containing continuous microtubule lattices were classified as intact zones, while regions with fragmented or dissolved microtubules were designated disrupted zones. The microtubule disruption index was calculated as the percentage of the total disrupted zone area relative to the combined area of intact and disrupted zones within each analyzed field [22].

2.11 Statistical analysis

The data were expressed as mean value ± standard deviation (SD). The analysis of differences between pairs of groups was conducted using a two-tailed t-test as proposed by Student, whereas comparisons across multiple groups were evaluated using one-way ANOVA, followed by Tukey’s post-hoc analysis. Analyses were performed in GraphPad Prism 8.0 (GraphPad Software, San Diego, CA, USA). All histograms were assessed using this methodology. The statistical examination was conducted via Stata 11.0 (SAS Inc, Cary, NC, USA). A significance level of P < 0.05 was considered indicative of statistical difference.

3 Results

3.1 LXA4 attenuates MIRI in ex vivo rat hearts

Histopathological analysis revealed significant myocardial damage in the I/R group, with pathology scores markedly elevated compared to controls (Table 1). LXA4 administration (100–400 μg/kg) dose-dependently reduced myocardial injury severity, achieving maximal protection at 200 μg/kg (##p < 0.01 vs I/R group). Notably, no additional benefit was observed at the 400 μg/kg dose, suggesting a ceiling effect in therapeutic efficacy (p > 0.05, 200 vs 400 μg/kg).

Table 1

Effect of LXA4 on pathological changes in I/R myocardium

Group	Dose (µg/kg)	Pathological grades
Group	Dose (µg/kg)	0	I	II	III	IV	P value
Control	—	7	1	0	0	0
I/R	—	0	0	2	2	4	**
I/R+LXA4	100	2	1	4	1	0	#
	200	1	5	2	0	0	##
	400	1	6	1	0	0	##

** vs control group (p < 0.01); # vs I/R group (p < 0.05); ## vs I/R group (p < 0.01).

Hemodynamic assessments demonstrated preserved coronary blood flow (CF) in LXA4-treated hearts post-I/R. While baseline CF remained comparable across groups, I/R injury induced a sharp decline in CF (Figure 1a). LXA4 treatment (100–400 μg/kg) restored CF to near-physiological levels, with 200 μg/kg yielding optimal recovery (##p < 0.05 vs I/R group). Biochemical analysis further corroborated these findings: serum cTnI and CK-MB levels, elevated 3.2-fold and 2.8-fold in the I/R group, respectively, were normalized by LXA4 in a dose-dependent manner (Figure 1b and c).

Figure 1

The application of LXA4 facilitates the mitigation of injury caused by I/R in isolated rat cardiac tissues. (a) Effect of LXA4 on coronary blood flow during I/R in isolated rat cardiac. (b) and (c) Effects of LXA4 on the content of cTnI and CK-MB after I/R in rats. ** vs control group (p < 0.01); # vs I/R group (p < 0.05); ## vs I/R group (p < 0.01).

Collectively, these data confirm successful induction of the I/R model and establish 200 μg/kg as the minimally effective dose for LXA4-mediated cardioprotection. This dose was selected for subsequent mechanistic studies to avoid potential off-target effects associated with higher concentrations.

3.2 LXA4 can restore microtubule expression and protect microtubule structure in I/R injury

Immunofluorescence analysis revealed a noteworthy contrast: in comparison to the control group (4.8 ± 0.9%), the microtubule rupture score in the I/R group exhibited a substantial increase to 48.5 ± 6.7%. Following treatment with LXA4 (200 μg/kg), the microtubule rupture score showed a marked reduction to 23.6 ± 3.6%. It is worth noting that no significant differences were observed between LXA4 alone group (200 μg/kg) (4.7 ± 1.1%) and the control group (Figure 2a and b). Complementing these results, β-tubulin expression was significantly reduced in the I/R group compared with the normal group, but treatment with LXA4 (200 μg/kg) markedly restored β-tubulin levels (Figure 2c and d).

Figure 2

LXA4 alleviates microtubule damage caused by myocardial ischemia in rats. (a) The microtubule rupture levels of Control group, LXA4 group, I/R group, and I/R+LXA4 group were detected by immunofluorescence; (b) Microtubule rupture score histogram. (c) and (d) The relative expression level of β-tubulin. ** vs control group (p < 0.01); ## vs I/R group (p < 0.01).

3.3 LXA4 can regulate the oxidative stress in I/R damage

I/R damage is frequently linked to oxidative stress, necessitating the assessment of key oxidative stress indexes such as SOD, GSH-Px, and MDA. The findings revealed notable alterations compared to the control group: in the I/R group, the antioxidant markers SOD (Figure 3a) and GSH-Px (Figure 3b) exhibited a significant decrease, whereas the oxidant indicator MDA (Figure 3c) demonstrated a marked increase. Following LXA4 treatment for I/R injury, there was a substantial increase in SOD and GSH-Px levels, accompanied by a significant decrease in MDA levels. These results strongly imply that oxidative stress plays a crucial role in I/R damage, and the administration of LXA4 can effectively ameliorate the I/R condition by reducing oxidative stress.

Figure 3

The application of LXA4 mitigates the harmful effects of oxidative stress induced by I/R. (a) Changes in SOD activity after I/R; (b) Changes in GSH-Px activity after I/R; (c) Changes in MDA content after I/R.** vs control group (p < 0.01); # vs I/R group (p < 0.05); ## vs I/R group (p < 0.01).

3.4 LXA4 enhanced the recovery from I/R damage through the Notch1-Nrf2 signaling pathway

The results show that the expression level of Notch1, Hes1, Nrf2, and β-tubulin in the I/R group were significantly reduced compared to the control group. However, after LXA4 treatment, the protein levels of Notch1, Hes1, Nrf2, and β-tubulin exhibited a significant upregulation (Figure 4a–e). This implies that LXA4 enhances the expression of β-tubulin, closely associated with the Notch1/Nrf2 signaling pathway.

Figure 4

LXA4 attenuates MIRI via the Notch1-Nrf2 signaling pathway in isolated rat hearts. (a) Representative Western blot images demonstrating protein expression levels of Notch1, Hes1, Nrf2, and β-tubulin across experimental groups. (b)–(e) Densitometric quantification of relative protein expression levels of Notch1 (b), Hes1 (c), Nrf2 (d), and β-tubulin (e). (f) Western blot analysis of Notch1, Hes1, Nrf2, and β-tubulin expression after DAPT (Notch1 inhibitor) administration. (g)–(j) Quantitative analysis of Notch1 (g), Hes1 (h), Nrf2 (i), and β-tubulin (j) expression after DAPT administration. (k) Western blot profiles showing protein expression of Notch1, Hes1, Nrf2, and β-tubulin after ML385 (Nrf2 inhibitor) administration. (l)–(o) Densitometric evaluation of Notch1 (l), Hes1 (m), Nrf2 (n), and β-tubulin (o) levels after ML385 administration. (p)–(s) Biochemical markers of myocardial injury and oxidative stress: (p) cTnI, (q) CK-MB, (r) SOD activity, and (s) MDA content. Data are presented as mean value ± SD (n = 6). ** vs control group (p < 0.01); # vs I/R group (p < 0.05); ## vs I/R group (p < 0.01); & vs I/R+LXA4 group (p < 0.05); && vs I/R+LXA4 group (p < 0.01).

Subsequently, we employed DAPT (a Notch1 inhibitor) and ML385 (an Nrf2 inhibitor). In comparison to the I/R+LXA4 group, the upregulation of Notch1, Hes1, Nrf2, and β-tubulin was significantly inhibited after the addition of DAPT (Figure 4f–j). Additionally, the expressions of Nrf2 and β-tubulin were significantly suppressed following the addition of ML385, while the upregulation of Notch1 and Hes1 remained unchanged compared to the I/R+LXA4 group (Figure 4k–o). This indicates that Nrf2 is a downstream protein of Notch1.

ELISA results demonstrated that upon the addition of inhibitors, in comparison to the I/R+LXA4 group, the levels of cTnI (Figure 4p), CK-MB (Figure 4q), and MDA (Figure 4s) significantly increased, while the content of SOD (Figure 4r) decreased significantly. These findings suggest that LXA4 regulates oxidative stress and microtubule expression, thereby alleviating I/R damage via the Notch1-Nrf2 signaling pathway.

4 Discussion

LXA4 has demonstrated potential in treating various conditions such as pulmonary bronchial dysplasia, psoriasis, subarachnoid hemorrhage, testicular torsion injury, sepsis-related liver function impairment, and MIRI [23,24]. Despite its efficacy across these ailments, the precise mechanism underlying LXA4’s effectiveness in the context of I/R injury are not yet fully understood.

Previous investigations have shed light on the complex aspects of I/R injury, implicating pathways like NF-κB, Keap1-Nrf2, HIF-1α/BNIP3, and mitochondrial dysfunction [25,26,27,28]. Furthermore, the intricate microtubule ultrastructure emerges as a critical factor in I/R damage. Myocardial ischemia and hypoxia instigate changes in ion channels, cellular morphology, structural impairment, disarray in microtubule organization, and even disruption of the cytoskeletal framework [29,30]. Our study observed a decline in antioxidant markers (SOD and GSH-Px) alongside an increase in the oxidation index MDA and the microtubule rupture score within the I/R group. Conversely, administration of LXA4 mitigated oxidative stress markers and attenuated microtubule rupture, along with regulating β-tubulin expression. These findings suggest that LXA4 shields against I/R injury by modulating oxidative stress. Notably, it also exhibits a regulatory effect on microtubules, possibly intertwined with its impact on oxidative stress pathways.

Recent investigations have highlighted the signaling pathways of Notch1 and Nrf2 as novel targets for myocardial protection [13]. Nrf2 plays a crucial role in mediating cellular responses to oxidative stress, effectively regulating the expression of key components involved in the antioxidant defense system, such as glutathione and thioredoxin [31,32]. Additionally, Nrf2 actively engages in the clearance of ROS, detoxification of both endogenous and exogenous substances, and the regeneration of NADPH [33,34,35]. In the presence of cellular oxidative stress, Nrf2 becomes activated, leading to the expression of downstream target genes such as HO-1, NQO-1, and GPX4. This activation, in turn, facilitates the elimination of accumulated ROS, consequently mitigating oxidative damage.

Additionally, Nrf2 is intricately linked with various signaling pathways, notably the Notch1 signaling pathway [13]. Upon ligand binding, Notch1 undergoes prompt cleavage and translocates into the nucleus, initiating the transcription of downstream target genes, including Hes1 and Nrf2. This process executes the antioxidant functions of Notch1 [36]. Notch1 target genes, Hes1 and Hes3, can elevate Nrf2 expression, reducing oxidative stress by limiting ROS formation [37]. Interestingly, Nrf2 binds directly to a functional antioxidant response element on the Notch1 promoter, thereby promoting Notch1 expression [38]. These findings underscore the coordinated interplay between the Notch1 and Nrf2 signal pathway, in maintaining cellular oxidative homeostasis. In our study, we employed the Notch1 inhibitor DAPT and Nrf2 inhibitor ML385 to regulate the Notch1 and Nrf2 signal pathway, exploring the intricacies of Notch1-Nrf2 interactions in myocardial protection [38,39]. Our study identified Notch1 as an upstream regulator of Nrf2, consistent with existing literature [40,41]. Furthermore, our findings demonstrate that LXA4 can modulate oxidative stress via the Notch1-Nrf2 signaling pathway. This regulation influences microtubule structure, ultimately mitigating I/R injury.

While our results demonstrate that the administration of DAPT and ML385 effectively attenuated the pathological processes, aligning with the inhibition of the Notch1 and Nrf2 pathways, respectively, it is important to consider the limitations of pharmacological inhibitors. DAPT, as a γ-secretase inhibitor, can potentially affect the cleavage of other substrates beyond Notch1, such as other Notch receptors (Notch2-4) or amyloid precursor protein. Similarly, while ML385 is a selective Nrf2 antagonist, its effects on interconnected signaling networks cannot be entirely ruled out. Therefore, although our pharmacological data strongly suggest the involvement of Notch1 and Nrf2, the observed effects could potentially involve off-target mechanisms. This underscores that inhibitor studies alone are not definitive proof of pathway order or exclusive involvement. To establish a more direct causal relationship, future studies employing genetic approaches, such as cell-specific knockout or knockdown of Notch1 and Nrf2, are essential to corroborate these findings. Despite this limitation, our data provide a solid pharmacological foundation for the functional roles of these pathways in our model and highlight their potential as therapeutic targets.

Recent advances in LXA4 research have further elucidated its role in modulating oxidative stress and inflammation through the Nrf2 pathway. LXA4 has been shown to restore oxidative stress-induced vascular endothelial cell injury by activating the Nrf2-HO-1 axis, thereby offering a promising strategy for managing venous thromboembolism and its complications [42]. Furthermore, LXA4 has been reported to protect against renal ischemia/reperfusion injury by promoting the IRG1/Nrf2 and IRAK-M-TRAF6 signaling pathways, providing a novel strategy for preventing and treating acute kidney injury [43].

In summary, the Nrf2 signaling pathway, in conjunction with Notch1 and LXA4, plays a pivotal role in the regulation of oxidative stress across various disease models. The intricate crosstalk between these pathways offers valuable insights into potential therapeutic targets for managing oxidative stress-related diseases. The continued exploration of these interactions holds promise for the development of novel therapeutic strategies aimed at mitigating the deleterious effects of oxidative stress in human health.

These findings suggest that LXA4, serving as a potential protective agent against I/R injury, may mitigate damage to the microtubule structure through the Notch1-Nrf2 signaling pathway. However, further investigation using transgenic cell or mouse models is necessary to fully be aware of the impact of the Notch1-Nrf2 pathway on the protective effects of LXA4 against MIRI. Future investigations will aim to explore the precise mechanism of Notch1-Nrf2 on LXA4-mediated protection against MIRI in cell models.

# These authors contributed equally to this work.

Acknowledgments

The authors are grateful for the reviewer’s valuable comments that improved the manuscript.

Funding information: This work was supported by the National Natural Science Foundation of China (Project numbers: 81460002, 81960012, 81860349, 82260374); Nature Foundation of Jiangxi Province (Project number: 20232BAB206002); Shanghai Jing an District Discipline Construction Project (2021PY03) and Key Supported Discipline Construction Project of Shibei Hospital (2025SBFC01); Shanghai Jing an District Health Research Project (2024MS11). Shanghai Jing an District Clinical Advantage Specialized Disease Construction Project (2024ZB02).
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and consented to its submission to the journal, reviewed all the results and approved the final version of the manuscript. X.Y., A.C., and Y.G. contributed equally to this work. X.Y., A.C., Y.G., H.C., and X.K. conceived and designed the study. X.Y., A.C., Y.G., J.X., J.L., L.W., and Y.F. performed experiments and analyzed the data. N.G. and L.Z. curated and validated datasets. X.Y., A.C., and Y.G. drafted the manuscript. H.C., X.K., J.X., and L.W. critically revised the text. H.C. and X.K. supervised the project and acquired funding.
Conflict of interest: Authors state no conflict of interest.
Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

[1] Zhu JJ, Yu BY, Fu CC, He MZ, Zhu JH, Chen BW, et al. LXA4 protects against hypoxic-ischemic damage in neonatal rats by reducing the inflammatory response via the IκB/NF-κB pathway. Int Immunopharmacol. 2020;89(Pt B):107095. 10.1016/j.intimp.2020.107095. Epub 2020/10/24. PubMed PMID: 33096360.Search in Google Scholar PubMed

[2] Zhou Y, Chen Y, Zhong X, Xia H, Zhao M, Zhao M, et al. Lipoxin A4 attenuates MSU-crystal-induced NLRP3 inflammasome activation through suppressing Nrf2 thereby increasing TXNRD2. Front Immunol. 2022;13:1060441. 10.3389/fimmu.2022.1060441. Epub 2022/12/27. PubMed PMID: 36569930; PubMed Central PMCID: PMCPMC9772058.Search in Google Scholar PubMed PubMed Central

[3] Xu S, Wu B, Zhong B, Lin L, Ding Y, Jin X, et al. Naringenin alleviates myocardial ischemia/reperfusion injury by regulating the nuclear factor-erythroid factor 2-related factor 2 (Nrf2)/System xc-/glutathione peroxidase 4 (GPX4) axis to inhibit ferroptosis. Bioengineered. 2021;12(2):10924–34. 10.1080/21655979.2021.1995994. Epub 2021/10/27. PubMed PMID: 34699317; PubMed Central PMCID: PMCPMC8809912.Search in Google Scholar PubMed PubMed Central

[4] Bai J, Wang X, Du S, Wang P, Wang Y, Quan L, et al. Study on the protective effects of danshen-honghua herb pair (DHHP) on myocardial ischaemia/reperfusion injury (MIRI) and potential mechanisms based on apoptosis and mitochondria. Pharm Biol. 2021;59(1):335–46. 10.1080/13880209.2021.1893346. Epub 2022/01/29. PubMed PMID: 35086399; PubMed Central PMCID: PMCPMC8797739.Search in Google Scholar PubMed PubMed Central

[5] Wang R, Wang M, Zhou J, Wu D, Ye J, Sun G, et al. Saponins in Chinese herbal medicine exerts protection in myocardial ischemia-reperfusion injury: Possible mechanism and target analysis. Front Pharmacol. 2020;11:570867. 10.3389/fphar.2020.570867. Epub 2021/02/19. PubMed PMID: 33597866; PubMed Central PMCID: PMCPMC7883640.Search in Google Scholar PubMed PubMed Central

[6] Das UN. Essential fatty acids and their metabolites in the pathobiology of inflammation and its resolution. Biomolecules. 2021;11(12):1873–903. 10.3390/biom11121873. Epub 2021/12/25. PubMed PMID: 34944517; PubMed Central PMCID: PMCPMC8699107.Search in Google Scholar PubMed PubMed Central

[7] Mei HX, Ye Y, Xu HR, Xiang SY, Yang Q, Ma HY, et al. LXA4 inhibits lipopolysaccharide-induced inflammatory cell accumulation by resident macrophages in mice. J Inflamm Res. 2021;14:1375–85. 10.2147/jir.S301292. Epub 2021/04/22. PubMed PMID: 33880053; PubMed Central PMCID: PMCPMC8052121.Search in Google Scholar PubMed PubMed Central

[8] Jiang S, Wan Q, Wang X, Di L, Li X, Kang R, et al. LXA4 attenuates perioperative neurocognitive disorders by suppressing neuroinflammation and oxidative stress. Int Immunopharmacol. 2023;123:110788. Epub 2023/08/18. 10.1016/j.intimp.2023.110788. PubMed PMID: 37591120.10.1016/j.intimp.2023.110788Search in Google Scholar PubMed

[9] Yang JX, Li M, Chen XO, Lian QQ, Wang Q, Gao F, et al. Lipoxin A(4) ameliorates lipopolysaccharide-induced lung injury through stimulating epithelial proliferation, reducing epithelial cell apoptosis and inhibits epithelial-mesenchymal transition. Respir Res. 2019;20(1):192. 10.1186/s12931-019-1158-z. Epub 2019/08/24. PubMed PMID: 31438948; PubMed Central PMCID: PMCPMC6704532.Search in Google Scholar PubMed PubMed Central

[10] Li Y, Yang B, Zhang X, Shen X, Ma Y, Jing L. Lycium barbarum polysaccharide antagonizes cardiomyocyte apoptosis by inhibiting the upregulation of GRK2 induced by I/R injury, and salvage mitochondrial fission/fusion imbalance and AKT/eNOS signaling. Cell Signal. 2022;92:110252. 10.1016/j.cellsig.2022.110252. Epub 2022/01/23. PubMed PMID: 35065240.Search in Google Scholar PubMed

[11] Pan H, Niu L, Wu Y, Chen L, Zhou X, Zhao Y. Lycium barbarum polysaccharide protects rats and cardiomyocytes against ischemia/reperfusion injury via Nrf2 activation through autophagy inhibition. Mol Med Rep. 2021;24(5):778–91. 10.3892/mmr.2021.12418. Epub 2021/09/10. PubMed PMID: 34498711; PubMed Central PMCID: PMCPMC8436221.Search in Google Scholar PubMed PubMed Central

[12] Xu H, Wan XD, Zhu RR, Liu JL, Liu JC, Zhou XL. Keap-NRF2 signaling contributes to the Notch1 protected heart against ischemic reperfusion injury via regulating mitochondrial ROS generation and bioenergetics. Int J Biol Sci. 2022;18(4):1651–62. 10.7150/ijbs.63297. Epub 2022/03/15. PubMed PMID: 35280686; PubMed Central PMCID: PMCPMC8898363.Search in Google Scholar PubMed PubMed Central

[13] Zhou XL, Wu X, Zhu RR, Xu H, Li YY, Xu QR, et al. Notch1-Nrf2 signaling crosstalk provides myocardial protection by reducing ROS formation. Biochem Cell Biol. 2020;98(2):106–11. 10.1139/bcb-2018-0398. Epub 2020/02/19. PubMed PMID: 32069075.Search in Google Scholar PubMed

[14] Li LC, Peng Y, Liu YM, Wang LL, Wu XL. Gastric cancer cell growth and epithelial-mesenchymal transition are inhibited by γ-secretase inhibitor DAPT. Oncol Lett. 2014;7(6):2160–4. 10.3892/ol.2014.1980. Epub 2014/06/17. PubMed PMID: 24932308; PubMed Central PMCID: PMCPMC4049710.Search in Google Scholar PubMed PubMed Central

[15] Yan L, Hu H, Feng L, Li Z, Zheng C, Zhang J, et al. ML385 promotes ferroptosis and radiotherapy sensitivity by inhibiting the NRF2-SLC7A11 pathway in esophageal squamous cell carcinoma. Med Oncol. 2024;41(12):309. 10.1007/s12032-024-02483-6. Epub 2024/11/13. PubMed PMID: 39511054; PubMed Central PMCID: PMCPMC11543766.Search in Google Scholar PubMed PubMed Central

[16] Shi X, Tao G, Ji L, Tian G, Sappanone A. Protects against myocardial ischemia reperfusion injury by modulation of Nrf2. Drug Des Dev Ther. 2020;14:61–71. 10.2147/dddt.S230358. Epub 2020/02/06. PubMed PMID: 32021092; PubMed Central PMCID: PMCPMC6955610.Search in Google Scholar

[17] Zhou W, Li S, Hao S, Zhang H, Li T, Li W, et al. Protective effect and mechanism of low P50 haemoglobin oxygen carrier on isolated rat heart. Artif Cell Nanomed Biotechnol. 2022;50(1):121–9. 10.1080/21691401.2021.2017947. Epub 2022/05/13. PubMed PMID: 35546079.Search in Google Scholar PubMed

[18] Xiong GZ, Ye KH, Huang JL, Ye CL. Effects of extracts of Ginkgo biloba leaves on apelin concentration and expressions in plasma and myocardium of rats with myocardial ischemia injury. Zhong Yao Cai. 2009;32(8):1238–41. Epub 2009/12/08. PubMed PMID: 19960946.Search in Google Scholar

[19] Dong L, Fan Y, Shao X, Chen Z. Vitexin protects against myocardial ischemia/reperfusion injury in Langendorff-perfused rat hearts by attenuating inflammatory response and apoptosis. Food Chem Toxicol. 2011;49(12):3211–6. 10.1016/j.fct.2011.09.040. Epub 2011/10/18. PubMed PMID: 22001368.Search in Google Scholar PubMed

[20] Salameh A, Keller M, Dähnert I, Dhein S. Olesoxime inhibits cardioplegia-induced ischemia/reperfusion injury. A study in Langendorff-perfused rabbit hearts. Front Physiol. 2017;8:324. 10.3389/fphys.2017.00324. Epub 2017/06/06. PubMed PMID: 28579963; PubMed Central PMCID: PMCPMC5437207.Search in Google Scholar PubMed PubMed Central

[21] Matsuura H, Kojima A, Fukushima Y, Xie Y, Mi X, Sabirov RZ, et al. Positive inotropic effects of ATP released via the maxi-anion channel in Langendorff-perfused mouse hearts subjected to ischemia-reperfusion. Front Cell Dev Biol. 2021;9:597997. 10.3389/fcell.2021.597997. Epub 2021/02/09. PubMed PMID: 33553176; PubMed Central PMCID: PMCPMC7859278.Search in Google Scholar PubMed PubMed Central

[22] Cao H, Wang Y, Wang Q, Wang R, Guo S, Zhao X, et al. Taxol prevents myocardial ischemia-reperfusion injury by inducing JNK-mediated HO-1 expression. Pharm Biol. 2016;54(3):555–60. 10.3109/13880209.2015.1060507. Epub 2015/08/14. PubMed PMID: 26270131.Search in Google Scholar PubMed

[23] Jia G, Wang X, Wu W, Zhang Y, Chen S, Zhao J, et al. LXA4 enhances prostate cancer progression by facilitating M2 macrophage polarization via inhibition of METTL3. Int Immunopharmacol. 2022;107:108586. 10.1016/j.intimp.2022.108586. Epub 2022/03/02. PubMed PMID: 35228032.Search in Google Scholar PubMed

[24] Zhang L, Tai Q, Xu G, Gao W. Lipoxin A4 attenuates the lung ischaemia reperfusion injury in rats after lung transplantation. Ann Med. 2021;53(1):1142–51. 10.1080/07853890.2021.1949488. Epub 2021/07/15. PubMed PMID: 34259112; PubMed Central PMCID: PMCPMC8281088.Search in Google Scholar PubMed PubMed Central

[25] Teodoro JS, Da Silva RT, Machado IF, Panisello-Roselló A, Roselló-Catafau J, Rolo AP, et al. Shaping of hepatic ischemia/reperfusion events: The crucial role of mitochondria. Cells. 2022;11(4):688–711. 10.3390/cells11040688. Epub 2022/02/26. PubMed PMID: 35203337; PubMed Central PMCID: PMCPMC8870414.Search in Google Scholar PubMed PubMed Central

[26] Du J, Liu L, Yu B, Hao F, Liu G, Jing H, et al. Clusterin (apolipoprotein J) facilitates NF-κB and Bax degradation and prevents I/R injury in heart transplantation. Int J Clin Exp Pathol. 2018;11(3):1186–96. Epub 2018/03/01. PubMed PMID: 31938213; PubMed Central PMCID: PMCPMC6958155.Search in Google Scholar

[27] Zhu N, Li J, Li Y, Zhang Y, Du Q, Hao P, et al. Berberine protects against simulated ischemia/reperfusion injury-induced H9C2 cardiomyocytes apoptosis in vitro and myocardial ischemia/reperfusion-induced apoptosis in vivo by regulating the mitophagy-mediated HIF-1α/BNIP3 pathway. Front Pharmacol. 2020;11:367. 10.3389/fphar.2020.00367. Epub 2020/04/16. PubMed PMID: 32292345; PubMed Central PMCID: PMCPMC7120539.Search in Google Scholar PubMed PubMed Central

[28] Deng S, Essandoh K, Wang X, Li Y, Huang W, Chen J, et al. Tsg101 positively regulates P62-Keap1-Nrf2 pathway to protect hearts against oxidative damage. Redox Biol. 2020;32:101453. 10.1016/j.redox.2020.101453. Epub 2020/02/15. PubMed PMID: 32057709; PubMed Central PMCID: PMCPMC7264471.Search in Google Scholar PubMed PubMed Central

[29] Severino P, D’Amato A, Pucci M, Infusino F, Birtolo LI, Mariani MV, et al. Ischemic heart disease and heart failure: Role of coronary ion channels. Int J Mol Sci. 2020;21(9):3167–84. 10.3390/ijms21093167. Epub 2020/05/06. PubMed PMID: 32365863; PubMed Central PMCID: PMCPMC7246492.Search in Google Scholar PubMed PubMed Central

[30] Goldblum RR, McClellan M, White K, Gonzalez SJ, Thompson BR, Vang HX, et al. Oxidative stress pathogenically remodels the cardiac myocyte cytoskeleton via structural alterations to the microtubule lattice. Dev Cell. 2021;56(15):2252–66.e6. 10.1016/j.devcel.2021.07.004. Epub 2021/08/04. PubMed PMID: 34343476; PubMed Central PMCID: PMCPMC8374671.Search in Google Scholar PubMed PubMed Central

[31] Yang Z, Tai Y, Lan T, Zhao C, Gao JH, Tang CW, et al. Inhibition of cyclooxygenase-2 upregulates the nuclear factor erythroid 2-related factor 2 signaling pathway to mitigate hepatocyte ferroptosis in chronic liver injury. J Clin Transl Hepatol. 2025;13(5):409–17. 10.14218/jcth.2024.00440. Epub 2025/05/19. PubMed PMID: 40385941; PubMed Central PMCID: PMCPMC12078174.Search in Google Scholar PubMed PubMed Central

[32] Yang D, Zhai C, Ren J, Bai J, Li T, Lu M, et al. Hydroxycitric acid inhibits ferroptosis and ameliorates benign prostatic hyperplasia by upregulating the Nrf2/GPX4 pathway. World J Urol. 2025;43(1):318. 10.1007/s00345-025-05637-x. Epub 2025/05/20. PubMed PMID: 40392347; PubMed Central PMCID: PMCPMC12092493.Search in Google Scholar PubMed PubMed Central

[33] Guo Z, Mo Z. Keap1-Nrf2 signaling pathway in angiogenesis and vascular diseases. J Tissue Eng Regen Med. 2020;14(6):869–83. 10.1002/term.3053. Epub 2020/04/27. PubMed PMID: 32336035.Search in Google Scholar PubMed

[34] Chen QM. Nrf2 for cardiac protection: pharmacological options against oxidative stress. Trends Pharmacol Sci. 2021;42(9):729–44. 10.1016/j.tips.2021.06.005. Epub 2021/08/02. PubMed PMID: 34332753; PubMed Central PMCID: PMCPMC8785681.Search in Google Scholar PubMed PubMed Central

[35] Ngo V, Duennwald ML. Nrf2 and oxidative stress: A general overview of mechanisms and implications in human disease. Antioxid (Basel). 2022;11(12):2345–71. 10.3390/antiox11122345. Epub 2022/12/24. PubMed PMID: 36552553; PubMed Central PMCID: PMCPMC9774434.Search in Google Scholar PubMed PubMed Central

[36] Li X, Zou F, Lu Y, Fan X, Wu Y, Feng X, et al. Notch1 contributes to TNF-α-induced proliferation and migration of airway smooth muscle cells through regulation of the Hes1/PTEN axis. Int Immunopharmacol. 2020;88:106911. 10.1016/j.intimp.2020.106911. Epub 2020/09/02. PubMed PMID: 32871474.Search in Google Scholar PubMed

[37] Ren BC, Zhang W, Zhang W, Ma JX, Pei F, Li BY. Melatonin attenuates aortic oxidative stress injury and apoptosis in STZ-diabetes rats by Notch1/Hes1 pathway. J Steroid Biochem Mol Biol. 2021;212:105948. 10.1016/j.jsbmb.2021.105948. Epub 2021/07/06. PubMed PMID: 34224859.Search in Google Scholar PubMed

[38] Ishikawa C, Mori N. ML385, a selective inhibitor of Nrf2, demonstrates efficacy in the treatment of adult T-cell leukemia. Leuk Lymphoma. 2025;66(4):721–32. 10.1080/10428194.2024.2441875. Epub 2024/12/17. PubMed PMID: 39689304.Search in Google Scholar PubMed

[39] Soni H, Matthews AT, Pallikkuth S, Gangaraju R, Adebiyi A. γ-secretase inhibitor DAPT mitigates cisplatin-induced acute kidney injury by suppressing Notch1 signaling. J Cell Mol Med. 2019;23(1):260–70. 10.1111/jcmm.13926. Epub 2018/11/09. PubMed PMID: 30407728; PubMed Central PMCID: PMCPMC6307805.Search in Google Scholar PubMed PubMed Central

[40] Qiu K, Ma C, Lu L, Wang J, Chen B, Mao H, et al. DAPT suppresses proliferation and migration of hepatocellular carcinoma by regulating the extracellular matrix and inhibiting the Hes1/PTEN/AKT/mTOR signaling pathway. J Gastrointest Oncol. 2021;12(3):1101–16. 10.21037/jgo-21-235. Epub 2021/07/24. PubMed PMID: 34295560; PubMed Central PMCID: PMCPMC8261317.Search in Google Scholar PubMed PubMed Central

[41] Xu C, Chen Y, Zhou Z, Yan Y, Fu W, Zou P, et al. ML385, an Nrf2 inhibitor, synergically enhanced celastrol triggered endoplasmic reticulum stress in lung cancer cells. ACS Omega. 2024;9(43):43697–705. 10.1021/acsomega.4c06152. Epub 2024/11/04. PubMed PMID: 39493971; PubMed Central PMCID: PMCPMC11525519.Search in Google Scholar PubMed PubMed Central

[42] Yang S, Zheng Y, Hou X. Lipoxin A4 restores oxidative stress-induced vascular endothelial cell injury and thrombosis-related factor expression by its receptor-mediated activation of Nrf2-HO-1 axis. Cell Signal. 2019;60:146–53. 10.1016/j.cellsig.2019.05.002. Epub 2019/05/07. PubMed PMID: 31059786.Search in Google Scholar PubMed

[43] Tie H, Kuang G, Gong X, Zhang L, Zhao Z, Wu S, et al. LXA4 protected mice from renal ischemia/reperfusion injury by promoting IRG1/Nrf2 and IRAK-M-TRAF6 signal pathways. Clin Immunol. 2024;261:110167. 10.1016/j.clim.2024.110167. Epub 2024/03/08. PubMed PMID: 38453127.Search in Google Scholar PubMed

Received: 2025-06-16

Revised: 2025-09-29

Accepted: 2025-09-30

Published Online: 2025-11-20

This work is licensed under the Creative Commons Attribution 4.0 International License.

Articles in the same Issue

https://doi.org/10.1515/biol-2025-1200

Keywords for this article

oxidative stress; ischemia/reperfusion; LXA4; microtubules; Notch1-Nrf2.

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