Advances in Drug Development for Myocardial Ischemia-Reperfusion Injury Targeting Antioxidant Mechanisms

Advances in Drug Development for Myocardial Ischemia-Reperfusion Injury Targeting Antioxidant Mechanisms | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 14 February 2026 V1 Latest version Share on Advances in Drug Development for Myocardial Ischemia-Reperfusion Injury Targeting Antioxidant Mechanisms Authors : Jingsong Wang , Heping Li , Qiong Shao , Yang Zhao , Xueqin Yang , Mei Fan , Heng Gan , Qian Tang , Shuang Jiang , and Jingwen Xie [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.177105279.92130027/v1 178 views 62 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Myocardial ischemia-reperfusion injury (MIRI) is a secondary injury that occurs upon the restoration of blood flow to ischemic myocardium, significantly diminishing the clinical benefits of reperfusion therapy. Excessive production of reactive oxygen species (ROS) and subsequent oxidative stress are recognized as central pathological mechanisms underlying MIRI. In recent years, significant progress has been made in the development of therapeutic agents targeting ROS scavenging and the modulation of oxidative stress. This review systematically summarizes recent advancements in MIRI interventions based on antioxidant mechanisms, including strategies for direct ROS elimination and the activation of endogenous antioxidant pathways. Through integrated target prediction and network analysis, the molecular basis and interactions of various antioxidant strategies are elucidated, highlighting compounds such as Honokiol as critical nodes within the intervention network. Additionally, utilizing the National Center for Biotechnology Information (NCBI) database, this work compiles and discusses the clinical progress of related antioxidant drugs in myocardial protection, offering a comprehensive overview and future perspectives. Ultimately, this review provides valuable insights for the future development of effective and low-toxicity anti-MIRI pharmaceutical agents. Keywords : Myocardial ischemia-reperfusion injury; ROS; Oxidative stress; Antioxidants Advances in Drug Development for Myocardial Ischemia-Reperfusion Injury Targeting Antioxidant Mechanisms Jingsong Wang 1† , Heping Li 1 † , Qiong Shao 2† , Yang Zhao 1 , Xueqin Yang 1 , Mei Fan 1 , Heng Gan 3 , Qian Tang 1* , Shuang Jiang 5* , Jingwen Xie 4,5* 1. Department of Pharmacy, Guangyuan Central Hospital, Affiliated Hospital of North Sichuan Medical College, Guangyuan, Sichuan, People’s Republic of China; 2. Department of Pharmacy, Ezhou Central Hospital, Ezhou, Hubei, People’s Republic of China; 3. Department of Pharmacy, Luzhou Hospital of Traditional Chinese Medicine, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 4. Department of Health, Chongqing Industry & Trade Polytechnic, Chongqing, People’s Republic of China; 5. College of Life Sciences, Chongqing Normal University, Chongqing, People’s Republic of China. †These authors contributed equally to this work and share first authorship.*Correspondence: Jingwen Xie, [email protected] ; Shuang Jiang, [email protected] ; Qian Tang, [email protected] . Abstract Myocardial ischemia-reperfusion injury (MIRI) is a secondary injury that occurs upon the restoration of blood flow to ischemic myocardium, significantly diminishing the clinical benefits of reperfusion therapy. Excessive production of reactive oxygen species (ROS) and subsequent oxidative stress are recognized as central pathological mechanisms underlying MIRI. In recent years, significant progress has been made in the development of therapeutic agents targeting ROS scavenging and the modulation of oxidative stress. This review systematically summarizes recent advancements in MIRI interventions based on antioxidant mechanisms, including strategies for direct ROS elimination and the activation of endogenous antioxidant pathways. Through integrated target prediction and network analysis, the molecular basis and interactions of various antioxidant strategies are elucidated, highlighting compounds such as Honokiol as critical nodes within the intervention network. Additionally, utilizing the National Center for Biotechnology Information (NCBI) database, this work compiles and discusses the clinical progress of related antioxidant drugs in myocardial protection, offering a comprehensive overview and future perspectives. Ultimately, this review provides valuable insights for the future development of effective and low-toxicity anti-MIRI pharmaceutical agents. Keywords : Myocardial ischemia-reperfusion injury; ROS; Oxidative stress; Antioxidants Introduction Myocardial ischemia is one of the leading causes of death globally, and while timely restoration of blood flow is essential to limit ischemic injury [1] , t the reperfusion process itself can induce myocardial ischemia-reperfusion injury (MIRI), paradoxically exacerbating tissue damage and worsening clinical outcomes [2] . The pathogenesis of MIRI involves multiple interconnected mechanisms, including calcium overload, inflammatory responses, energy metabolism disturbances, and oxidative stress. Among these, excessive reactive oxygen species (ROS)-induced oxidative stress is considered a central pathological event [1, 3] . Under normal physiological conditions, ROS function as signaling molecules in cellular transduction pathways. These species originate from both exogenous sources, such as cigarette smoke and environmental pollutants, and endogenous processes, including mitochondrial aerobic respiration, inflammatory responses, and high-energy electron transfer [4, 5] . During ischemia and reperfusion, the balance between ROS production and elimination is disrupted, leading to significant accumulation and consequent oxidative stress injury [6] . ROS encompass various chemical species, including hydroxyl radicals (·OH), superoxide anions (O 2 – ), and hydrogen peroxide (H 2 O 2 ) [7] . These reactive molecules can damage lipids, proteins, and nucleic acids [8] , disrupting cellular integrity and interfering with signaling pathways, ultimately leading to various forms of cell death, such as apoptosis and necrosis [9, 10] . Notably, oxidative stress contributes not only to MIRI but also plays a pivotal role in various age-related pathologies, including neurodegenerative diseases, diabetes, and hypertension [11-17] . In the context of MIRI, the overproduction of ROS coupled with compromised endogenous antioxidant capacity promotes oxidative damage, leading to myocardial dysfunction and structural remodeling [18] . Consequently, pharmacological interventions using exogenous antioxidants to scavenge ROS or enhance intrinsic defense mechanisms have emerged as promising therapeutic strategies for mitigating MIRI. Current antioxidant therapeutic approaches have evolved from simple radical scavenging to multi-level systematic interventions. These mechanisms include direct neutralization of existing ROS by antioxidant compounds and activation of endogenous antioxidant defense systems through regulation of signaling pathways, thereby promoting the expression of protective proteins such as heme oxygenase-1 (HO-1) and superoxide dismutase (SOD) [19] . Particularly noteworthy are dual-mechanism antioxidants, which demonstrate synergistic therapeutic potential by combining direct free radical scavenging with activation of endogenous antioxidant pathways [20] . Additionally, research has expanded to include nanotechnology-based drug delivery systems for enhanced targeting efficiency, as well as interventions targeting novel regulated cell death pathways such as ferroptosis. These emerging directions provide new theoretical foundations for MIRI prevention and treatment [21-23] . This review systematically summarizes recent advances in drug development aimed at alleviating MIRI through antioxidant mechanisms, including their modes of action, molecular targets, design strategies, and clinical research progress. The goal is to offer valuable insights for the development of effective and low-toxicity therapeutic agents against MIRI. 2 Direct ROS scavenging to mitigate MIRI Direct scavenging of ROS is a straightforward antioxidant strategy for alleviating MIRI. Compounds in this category rapidly react with ROS, converting them into stable, non-toxic products, effectively reducing intracellular ROS levels and mitigating oxidative stress damage [20, 24, 25] . An ideal direct antioxidant agent should achieve effective concentrations at the injury site and efficiently react with ROS [26] . These agents can primarily be classified based on their origins and structural characteristics into vitamins, trace elements, natural products, and chemically synthesized drugs (Table 1). 2.1 Vitamins Vitamins play essential roles in maintaining normal physiological functions [27, 28] . While vitamin deficiencies are linked to various diseases, direct research into their therapeutic application for specific conditions remains relatively limited. Vitamin C (ascorbic acid), with its unique enol hydroxyl groups, demonstrates strong reducing capacity. It efficiently scavenges free radicals, including O 2 – , hydroperoxyl radicals (HOO·), and (·OH), making it a significant antioxidant in plasma [29] . Studies have shown that vitamin C not only reduces intracellular ROS levels but also diminishes infarct size following myocardial reperfusion in experimental models, suggesting its potential therapeutic value in MIRI treatment [30] . Beyond direct free radical scavenging, vitamin C may also provide cardioprotective effects by modulating relevant antioxidant signaling pathways [31-40] . Furthermore, the fabrication of electrospun polycaprolactone (PCL) fibers containing varying concentrations of vitamin C presents a novel approach to modulating the highly oxidized microenvironment following myocardial infarction [41] . Vitamin E, a fat-soluble antioxidant, is predominantly distributed within biological membranes as tocopherol. It neutralizes free radicals directly, protecting membrane lipids from ROS-induced damage [42] . Pre-administration of vitamin E has been shown to significantly reduce myocardial ischemia in MIRI model mice and suppress neutrophil activity, suggesting its potential as a prophylactic agent against MIRI [43] . 2.2 Trace elements Selenium (Se), an essential trace element, not only directly scavenges ROS [44] but also serves as a key component of glutathione peroxidase (GSH-Px), facilitating the synthesis of this enzyme [45] . GSH-Px catalyzes the conversion of glutathione (GSH) to oxidized glutathione (GSSG), reducing toxic peroxides to harmless hydroxyl compounds [46] . Elevating selenium levels enhances GSH-Px activity, protecting cellular membranes from oxidative damage [47] . Conversely, selenium deficiency reduces both serum selenium levels and GSH-Px activity, potentially triggering oxidative stress and apoptosis via mitochondrial pathways, ultimately leading to cardiac dysfunction [48] . Maintaining mitochondrial integrity and energy metabolism is essential in treating myocardial dysfunction [49] . Zinc (Zn), another vital trace element, is involved in numerous physiological processes, including metabolism, signal transduction, and gene regulation [50] . Zinc deficiency exacerbates oxidative stress and worsens ROS-induced MIRI, highlighting its role in maintaining cardiac redox balance [51] . 2.3 Natural products The exploration of active constituents from natural plants represents a significant approach in drug discovery. Many natural products can directly interact with free radicals [52] , providing protection against MIRI by mitigating oxidative stress damage [53] . For instance, Honokiol, a natural phenolic compound isolated from the bark of Magnolia officinalis, demonstrates a broad spectrum of biological activities, including antioxidant, anti-inflammatory, antitumor, antimicrobial, and neuroprotective effects [54-56] . Although its protective effects against ischemia-reperfusion injury have been documented in organs such as the kidneys and brain [55] , studies focusing on the heart remains relatively limited. Studies by Zhipeng Tan et al. revealed that Honokiol reduces ROS generation and attenuates mitochondrial damage in the myocardium of MIRI mice, highlighting its distinct cardioprotective effects [57] . In addition to its direct ROS-scavenging capability, Honokiol has been shown to mitigate MIRI through the regulation of antioxidant signaling pathways [58-61] . Additionally, Esculetin, a coumarin derivative, has been found to effectively reduce intracellular ROS levels and the expression of pro-inflammatory cytokines [62] , thereby inhibiting cardiomyocyte apoptosis and necrosis [63] . Colchicine may alleviate MIRI-associated microvascular obstruction (MVO), potentially through mechanisms involving suppression of cardiomyocyte apoptosis and reduction of ROS levels [64] . Further studies have uncovered the cardioprotective potential of various other natural products. Sinomenine, an alkaloid extracted from the root of S. acutum, has been shown to reduce myocardial infarct size and improve cardiac function in MIRI models. Its protective effects are primarily mediated by inhibiting the generation of MDA and ROS, increasing GSH expression, attenuating inflammatory cytokines, and reducing the expression of apoptotic proteins [65] . Similarly, pretreatment with Indole-3-Carbinol (I3C), a compound found abundantly in cruciferous vegetables, significantly decreased infarct size and myocardial enzyme release in MIRI mice. It alleviated oxidative stress by enhancing total antioxidant capacity while reducing MDA and ROS levels. Additionally, it downregulated the expression of inflammatory cytokines such as TNF-α, IL-1β, and IL-6, and modulated Bcl-2/Bax proteins to inhibit apoptosis [66] . Moreover, geraniin, a polyphenol derived from the fruit peel of Nephelium lappaceum L., attenuated isoproterenol (ISO)-induced cardiac hypertrophy by suppressing inflammation, oxidative stress, and cellular apoptosis [67] , indicating its potential therapeutic value in MIRI. 2.4 Synthetic drugs Edaravone, a free radical scavenger approved in 2004 for treating cerebral ischemia-reperfusion injury, effectively inhibits lipid peroxidation and ameliorates cellular damage induced by ischemia and hypoxia [68] . Subsequent studies have confirmed its therapeutic potential against ischemia-reperfusion injury in multiple organs, including the heart, liver, and kidneys [69] . In MIRI models, Edaravone significantly reduces myocardial infarct size, demonstrating substantial cardioprotective efficacy [70] . Further clinical investigation (a phase IV clinical trial) showed that Edaravone effectively reduces oxidative stress levels in patients with MIRI, highlighting its potential clinical value [71] . Other research has indicated that Doxycycline positively modulates the oxidative and antioxidative balance in left ventricular tissue and blood samples, enhancing total antioxidant capacity [72] . Table 1 Compounds of Directly Scavenge ROS Vitamin C Direct ROS Scavenging GSK3B [30] Vitamin E Direct ROS Scavenging AKT1, CNR1, CNR2, PSEN1, ESR1… [43] Se GSH-PX / [47] Zn / / [51] Honokiol Direct ROS Scavenging ALOX5, CNR1, CNR2, CA2, BRAF… [57] Esculetin Direct ROS Scavenging XDH, EGFR, CA12, CA9, AKR1B1… [63] Colchicine Direct ROS Scavenging TUBB1, HDAC6, HDAC1, HDAC3 [64] Edaravone Direct ROS Scavenging APP, NT5E, CA9, CA2, FKBP1A… (55) Doxycycline Direct ROS Scavenging ESR2, MMP13, MMP2, GRK6, TDP1… [72] Sinomenine / MAPK8, ROCK2, ROCK1, NQO1, MTOR… [65] I3C / GSR, AOC3, MIF, CES1, CES2… [66] Geraniin / / [67] 2.5 Comparative analysis In summary, while vitamins, trace elements, natural products, and synthetic drugs all confer cardioprotective effects through direct ROS scavenging, they differ in their mechanisms of action, efficacy, and stages of clinical development, highlighting the diversity of antioxidant strategies. Vitamins and trace elements, as essential nutrients, have well-defined mechanisms and high safety profiles. However, their efficacy as monotherapies in complex pathological conditions is often limited, and their therapeutic window depends on the body’s homeostatic balance. Consequently, their clinical application is mainly focused on prevention or foundational adjuvant therapy [73, 74] . In contrast, natural products like Honokiol and Sinomenine generally offer synergistic benefits by engaging multiple protective pathways. They not only inhibit ROS but also protect through anti-inflammatory and anti-apoptotic mechanisms, demonstrating broader therapeutic potential in research. However, their translation into standardized therapeutics faces major challenges, including complex chemical compositions and structures [75] , suboptimal pharmacokinetics [76] , and difficulties in quality control and standardization [77] . To clarify the differences in translational potential between natural products and synthetic drugs, a systematic comparison of Honokiol and Edaravone is presented (Table 2), representing two distinct developmental pathways for antioxidant agents. Edaravone, a synthetic drug with an established mechanism, offers advantages such as rapid onset, potent efficacy, and a well-defined clinical translation pathway. Its well-documented pharmacokinetic and safety data provide a solid foundation for exploring new indications, such as MIRI [78] . In contrast, Honokiol, a natural product, stands out for its network-like mechanisms of action and multifaceted therapeutic effects, which may be particularly effective for complex pathologies like MIRI, where multiple factors are involved. However, its primary translational challenges stem from chemical complexity, undefined pharmacokinetics in humans, and a lack of clinical efficacy data. Future research could explore combining the rapid, potent ROS scavenging of Edaravone with the multi-pathway regulatory advantages of Honokiol-like agents to achieve synergistic efficacy. Alternatively, utilizing emerging technologies, such as nanodelivery systems, to enhance the solubility, targeting, and stability of natural products, along with comprehensive studies on their human mechanisms of action and safety profiles, will be critical for advancing these multi-target agents toward clinical application. Table 2 Systematic Comparison Between Honokiol and Edaravone in Treatment of MIRI Source A natural small-molecule phenolic compound derived from the bark of Magnolia officinalis [54] . A chemically synthesized pyrazolone-type free radical scavenger; an approved drug [68] . Antioxidant Mechanism Directly scavenges ROS [57] , Activates pathways such as SIRT1/Nrf2 [55, 58] and PI3K/Akt [59] . Directly and efficiently neutralizes ROS like hydroxyl radicals (·OH), interrupting the free radical cascade damage [68] . Modulation of Other Pathological Processes Exerts anti-inflammatory, anti-apoptotic, and autophagy-modulating effects [60, 61] . Possesses certain secondary anti-inflammatory and anti-apoptotic effects [70, 79] . Efficacy in MIRI Models Reduces myocardial infarct size, ameliorates cardiac function, and inhibits cardiomyocyte apoptosis, among other effects [59] . Significantly reduces myocardial infarct size and alleviates oxidative stress damage [79] . Clinical Research Status and Safety Status: No clinical trials for cardiovascular indications. Safety: systematic human safety data are lacking. Status: An approved drug, marketed in Japan, China, and other countries for acute cerebral infarction [78] . A Phase IV clinical trial for MIRI has been conducted [71] , but this indication is not yet formally approved. Safety: The safety profile is relatively well-defined. Advantages and Challenges Advantages: Multi-target and multi-effect synergistic actions, potentially better suited for the complex pathology of MIRI. Challenges: Chemical and mechanistic complexity, undefined human pharmacokinetics and safety, and a lack of clinical translation evidence. Advantages: Well-defined mechanism, rapid onset, potent efficacy, with comprehensive pharmaceutical, safety, and partial clinical efficacy data, enabling a clear clinical translation pathway. Challenges: Mechanism is relatively single-target, which may limit efficacy ceilings in complex diseases. Expanding to new indications as an approved drug still requires large-scale clinical trials. 3 Attenuation of MIRI by upregulating antioxidant proteins Beyond direct ROS scavenging, another important antioxidant strategy involves the pharmacological upregulation of endogenous antioxidant proteins, enhancing the cell’s intrinsic defense against oxidative damage (Table 3). Key mediators in this process include HO-1 and SOD [80] . SOD plays a pivotal role in reducing oxidative damage by catalyzing the conversion of O 2 – into H 2 O 2 and oxygen [81] . Salidroside, an extract from the natural plant Rhodiola rosea, demonstrates protective effects in MIRI models, with its mechanism closely linked to the inhibition of ROS generation and the enhancement of SOD activity [82, 83] . Building upon this, Zongyuan Wang et al. synthesized a series of Salidroside analogs and confirmed their ability to ameliorate myocardial injury by reducing oxidative stress in an LPS-induced cellular damage model [84] . Flavonoids play a positive role in this pathway. Scutellarin increases SOD levels in cardiomyocytes, enhances the JAK2/STAT3 signaling pathway, downregulates the expression of pro-apoptotic factors Bax and caspase-3, and improves cell survival, thereby providing myocardial protection [85] . Activation of the STAT3 pathway is particularly beneficial for maintaining mitochondrial homeostasis [86] and mitigating oxidative stress injury [87] during MIRI. Another flavonoid, naringin (NRG), elevates the activities of SOD, catalase (CAT), and citrate synthase, reduces ROS production, and modulates the Bax/Bcl-2 ratio, contributing to its cardioprotective effects [88] . Furthermore, glycyrrhizic acid (GA) has been shown to inhibit ROS generation during MIRI [89] . Triptolide, an epoxyditerpene lactone primarily known for its anti-inflammatory and immunosuppressive properties [90] , has been less studied for its antioxidant effects. However, Bin Yang et al. demonstrated that Triptolide not only inhibits ROS production and subsequent lipid peroxidation but also enhances the activities of CAT and SOD, thereby reducing intracellular ROS levels and providing myocardial protection [91] . Among synthetic agents, Amifostine, a first-generation cytoprotective drug approved by the FDA, is primarily used clinically to mitigate side effects associated with radiotherapy and chemotherapy [92] . In a MIRI mouse model, Amifostine pretreatment was found to significantly increase SOD expression, reduce malondialdehyde (MDA) content, and decrease myocardial infarct size, showing clear cardioprotective effects [93] . Similarly, retinol palmitate, a derivative of Vitamin A commonly used for corneal protection [94] , was investigated for its potential in MIRI by Luyuan Tao et al. Their research revealed promising cardioprotective outcomes, with mechanistic studies confirming that this compound enhances the activity of SOD-related proteins and reduces MDA levels, thereby alleviating oxidative stress [95] . Table 3 Compounds Activating Antioxidant Enzymes Salidroside SOD TYR, CA2, CA7, CA1, CA3… [82, 83] Scutellarin SOD AKR1B1, ADORA1, XDH, TNF, IL2… [85] Naringin SOD CYP19A1, SLC5A4, SRD5A1, SLC28A3, SLC5A2… [88] Glycyrrhizic acid Hippo/YAP / [89] Triptolide SOD PTGS2, AR, JUN, PRKCA, PDE4D… [91] Amifostine SOD DRD3 [93] Retinol palmitate SOD ALOX5, SF3B3, PRKCA, CYP19A1, AR… [95] 4 Mitigation of MIRI through activation of antioxidant signaling pathways In addition to direct antioxidant strategies, targeting endogenous antioxidant signaling pathways has emerged as an important avenue for MIRI intervention. Agents that activate these pathways indirectly enhance cellular antioxidant capacity by initiating specific signaling cascades, thus promoting ROS clearance [96] . Their systemic and sustained effects make them promising therapeutic candidates [97] . Current research has identified several key signaling pathways that play pivotal roles in counteracting oxidative stress and alleviating MIRI. 4.1 The PI3K/Akt signaling pathway The PI3K/Akt pathway is central to a wide range of physiological processes, including cell proliferation, differentiation, apoptosis, and metabolism [98] . Its activation begins with the specific phosphorylation of the 3-hydroxyl group of phosphatidylinositol by phosphoinositide 3-kinase (PI3K), leading to the translocation of protein kinase B (Akt) from the cytoplasm to the cell membrane, where it is subsequently activated [99, 100] . Activated Akt then regulates downstream target proteins, influencing critical cellular functions such as apoptosis, proliferation, differentiation, and migration [101] . Studies indicate that Akt activation also confers antioxidant effects [102] . Furthermore, the PI3K/Akt pathway is closely involved in apoptosis during ischemia [103] , and its activation can effectively inhibit oxidative stress, protect mitochondrial function, and counteract MIRI [104] (Table 4). For example, the traditional Tibetan medicine Rhodiola Granules (RG) exerts its effects partly through this mechanism [87] . Several drugs confer protection in MIRI through PI3K/Akt pathway activation. Clemastine Fumarate, an H1 receptor antagonist [105] , was found to downregulate Toll-like receptor 4 (TLR4) protein expression while upregulating PI3K/Akt protein levels in cardiomyocytes, suggesting that its protective effect against MIRI involves PI3K/Akt activation [106] . Tanshinone IIA, isolated from the Chinese herb Salvia miltiorrhiza, possesses free radical-scavenging and antioxidant properties and can significantly reduce ischemic injury [107] . Research by Qiang Li et al. further elucidated that its protective mechanism is linked to PI3K/Akt pathway activation and a reduction in intracellular ROS levels, highlighting its potential for therapeutic development [108] . Urolithin A, a natural metabolite produced by gut microbiota from ellagitannins found in pomegranates and other fruits [109] , has been shown to improve mitochondrial and muscle function, enhancing strength and endurance during aging [110] . Lu Tang et al. demonstrated that Urolithin A alleviates cardiomyocyte damage, reduces infarct size, decreases cell mortality, and enhances cellular antioxidant capacity. These protective effects were reversed by PI3K/Akt inhibitors, confirming the central role of this pathway in its mechanism of action [111] . Apart from its traditional use as an expectorant and antitussive agent [112] , the flavonoid Quercetin exhibits various cardiovascular protective effects, including coronary vasodilation, lipid-lowering activity, and enhanced coronary blood flow [113, 114] . Hui Liu et al. found that Quercetin reduces ROS levels, inhibits inflammatory responses and apoptosis, with its myocardial protection in MIRI involving the activation of the PI3K/Akt antioxidant pathway [115] . Table 4 Compounds Activating the PI3K/Akt Signaling Pathway Clemastine Fumarate PI3K/Akt KCNH2, HRH1, CHRM1, OPRM1, OPRK1… [106] TanshinoneⅡA PI3K/Akt AKR1B1, CES1, TERT, PTPN6, CES2… [108] Urolithin A PI3K/Akt XDH, ESR1, ESR2, CA12, CA9… [111] Quercetin PI3K/Akt NOX4, AVPR2, AKR1B1, XDH, MAOA… [115] 4.2 The Nrf2 signaling pathway The nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, regulated by the interaction between Kelch-like ECH-associated protein 1 (Keap1) and Nrf2, plays a central role in cellular defense against oxidative stress and the maintenance of redox homeostasis [96, 116] . Under normal physiological conditions, Nrf2 binds to Keap1 and undergoes ubiquitin-mediated degradation. Upon exposure to electrophilic agents or antioxidant stimuli, conformational changes in specific cysteine residues of Keap1 lead to Nrf2 dissociation, stabilization, and subsequent nuclear translocation. Within the nucleus, Nrf2 binds to the antioxidant response element (ARE), initiating the transcription of various phase II detoxifying enzymes and antioxidant proteins, including HO-1, NAD(P)H quinone dehydrogenase 1 (NQO1), and γ-glutamylcysteine synthetase (γ-GCS), thus enhancing the cellular antioxidant capacity [97] (Table 5). Hyperoside, a flavonoid extracted from Rhododendron species and used in traditional medicine, demonstrates significant anti-inflammatory [117] and antioxidant activities [118] . Jiayin Hou et al. investigated the therapeutic effects of Hyperoside on MIRI and found that pretreatment with Hyperoside improved cardiac function in rats, activated the Nrf2 pathway, reduced intracellular ROS levels, attenuated myocardial oxidative damage, and decreased apoptosis, thus showing substantial therapeutic efficacy against MIRI [119] . Astragaloside IV, a major active constituent of Astragalus membranaceus, possesses a range of pharmacological properties, including anti-inflammatory and antioxidant effects [120, 121] . Miaomiao Jiang et al. reported that pretreatment with Astragaloside IV significantly reduced myocardial infarct size, enhanced cardiac systolic and diastolic function, and suppressed the release of creatine kinase and lactate dehydrogenase. Mechanistic studies indicated that its cardioprotective effects are linked to Nrf2 pathway activation and the enhanced expression of antioxidant proteins such as HO-1 [122] . The metabolic intermediate L-(-)-Malic Acid also shows antioxidant potential. Shiao Ding et al. demonstrated that L-Malic Acid reduces myocardial infarct size, inhibits the expression of inflammatory factors, and likely exerts protective effects through the inhibition of lactate dehydrogenase and the promotion of Nrf2 expression and nuclear translocation [123] . In addition to the compounds mentioned above, several other natural products have shown promise in alleviating MIRI through Nrf2 pathway activation. For instance, Oleuropein (OP) activates Nrf2-related pathways and inhibits autophagy [124] . Açai berry treatment reduced myocardial injury markers and infarct size [125] . Cinnamaldehyde (CA), a key component of cinnamon, exhibited clear cardioprotective effects against MIRI [126] . Neferine, extracted from the green embryos of Nelumbo nucifera seeds, alleviates myocardial injury by suppressing apoptosis, oxidative stress, and mitochondrial dysfunction [127] . Kinsenoside (KD) shows antioxidant and vascular protective properties [128] . Fucoxanthin (FX), a carotenoid abundant in brown seaweed, mitigates MIRI by inhibiting ferroptosis through the Nrf2 pathway [129] . Additionally, Rhodiola wallichiana var. cholaensis (RW) [130] and Stachydrine (STA), an active constituent of Leonurus heterophyllus [131] , have been reported to activate the Nrf2 pathway, reducing oxidative stress and protecting cardiomyocytes in both in vivo and in vitro models. Notably, some natural products, such as Neferine and FX, demonstrate multi-target potential by concurrently activating the Nrf2 pathway and maintaining mitochondrial homeostasis [127, 129] . In summary, antioxidant therapy targeting the Nrf2 signaling pathway holds broad therapeutic potential for mitigating MIRI. Table 5 Compounds Activating the Nrf2 Signaling Pathway Hyperoside Nrf2 signaling pathway AKR1B1, CA2, CA7, CA12, CA4… [119] Astragaloside IV Nrf2 signaling pathway / [122] L-(-)-Malic Acid Nrf2 signaling pathway EGLN1, ACLY, CHRNA7, FDFT1 [123] Oleuropein Nrf2 signaling pathway IL2, ADORA1, ADORA2A, ADORA2B, ADORA3 [124] Cinnamaldehyde Nrf2 signaling pathway TRPA1, HCAR2, F3, ADH1B, ADH1C… [126] Neferine Nrf2 signaling pathway DRD2, SLC6A3, DRD1, SLC47A1, CHRNA4… [127] Kinsenoside Nrf2 signaling pathway HTR2B, ADRA2A, ADRA2C, ADRA2B, DRD1… [128] Fucoxanthin Nrf2 signaling pathway / [124] Stachydrine Nrf2 signaling pathway ACE, REN, SLC1A2, F2, LTA4H, NR1H4 [131] 4.3 The AMPK signaling pathway AMP-activated protein kinase (AMPK) serves as a central regulator of cellular energy metabolism [132] . This kinase can be activated by various stimuli, including cellular stress, exercise, and hormonal signals [133] . During MIRI, oxidative stress induces prolonged opening of the mitochondrial permeability transition pore (mPTP), resulting in mitochondrial dysfunction. AMPK activation effectively suppresses excessive mitochondrial ROS production during reperfusion and prevents sustained mPTP opening, thus preserving mitochondrial structure and function [134] . Consequently, AMPK plays a critical role in mitigating MIRI by maintaining mitochondrial homeostasis and balancing cardiomyocyte energy metabolism [135] (Table 6). Pramipexole, a medication commonly used for Parkinson’s disease treatment [136] , was investigated by Yingli Mo et al., who demonstrated that in both MIRI mouse models and hypoxic H9c2 cells, pramipexole exerted preventive and therapeutic effects against myocardial injury through activation of the AMPK signaling pathway [115] . Isoliquiritigenin, a chalcone compound commonly found in various foods and tobacco [137] , was studied by Xiaoyu Zhang et al., who measured ROS levels and cardiomyocyte contractile function. They found that this natural compound protected the heart against ischemic injury, potentially through mechanisms associated with AMPK pathway activation [138] . Dexmedetomidine (DEX), a highly selective α2-adrenergic receptor agonist, alleviates MIRI by suppressing mitophagy [139] . Further research indicated that combined administration of DEX and propofol (PPF) reduced MDA and ROS levels while enhancing SOD activity in rat models. These cardioprotective effects appear to be closely related to AMPK pathway activation [140] . Additionally, pachymic acid (PA), a lanostane-type triterpenoid, promoted the phosphorylation of IRS-1, Akt, and AMPK proteins in a dose-dependent manner. By activating the AMPK pathway, PA inhibited cardiomyocyte ferroptosis, thereby alleviating MIRI [141] . Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, activated mitophagy through the AMPK-PINK1/Parkin signaling pathway, demonstrating protective effects against MIRI in animal models [142] . Table 6 Compounds Activating the AMPK Signaling Pathway Pramipexole AMPK signaling pathway DRD2, DRD4, DRD3, PNMT, ESR2… [115] Isoliquiritigenin AMPK signaling pathway AKR1B1, CHRNA7, EGFR, TERT, ABCG2… [138] Dexmedetomidine AMPK signaling pathway ADRA2C, ADRA1D, TAAR1, HRH3, HRH4… [140] Pachymic Acid AMPK signaling pathway PTGES, PTPN1, PTPN2, HSD11B1, CES2… [141] Dapagliflozin AMPK-PINK1/parkin signalling pathway SLC5A4, SLC5A2, SLC5A1, ADK, ADORA2A… [142] 4.4 The MAPK signaling pathway The mitogen-activated protein kinase (MAPK) signaling pathway is a critical intracellular system that regulates cell growth, development, division, and death [143] . This pathway comprises three primary branches: extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK [144] . Notably, ROS can act as second messengers to activate the MAPK pathway, which, in turn, modulates the cellular redox state, creating a complex feedback loop that influences various pathological processes, including cell death [145] . The MAPK pathway typically does not function in isolation but interacts extensively with other signaling networks, forming an intricate regulatory system. For example, in the MAPK-PI3K/Akt interplay, activated Akt can directly phosphorylate the Ser83 site of Apoptosis Signal-regulating Kinase 1 (ASK1), a key upstream kinase of MAPK, altering its conformation and inactivating it. This prevents the downstream phosphorylation and activation of p38 MAPK and JNK, thereby reducing the initiation of the ROS-mediated mitochondrial apoptotic pathway [146-148] . Conversely, during MIRI, excessively activated p38 MAPK and JNK can phosphorylate the Thr308/Ser473 sites of Akt, inhibiting its downstream anti-apoptotic signaling [35, 149] . In the interaction between MAPK and the Nrf2 pathway, ERK1/2 can specifically phosphorylate Nrf2 at the Ser40 site, promoting its dissociation from Keap1 and facilitating its nuclear translocation to initiate the expression of antioxidant proteins such as HO-1 and NQO1 [150, 151] . Meanwhile, p38 MAPK enhances Nrf2 protein stability by inhibiting its ubiquitination-mediated degradation, thereby strengthening the cardiomyocyte’s resistance to oxidative stress [152, 153] . In summary, the PI3K/Akt pathway primarily promotes cell survival by inhibiting pro-apoptotic MAPK signals, while the Nrf2 pathway relies on MAPK-mediated positive regulation to enhance antioxidant capacity. The interactions among these pathways are likely to represent a key molecular mechanism for mitigating MIRI. Given the pivotal role of the MAPK pathway in the regulatory network of MIRI, targeting this pathway has emerged as a promising therapeutic strategy (Table 7). Several studies indicate that modulating the MAPK pathway effectively alleviates MIRI. For instance, All-Trans retinoic acid (ATRA) has been shown to protect against MIRI by suppressing the activities of kinases such as JNK and ERK, thereby downregulating MAPK signaling, reducing ROS generation, and exerting anti-apoptotic effects [154] . Hirsutine may protect cardiomyocytes by inhibiting mitochondrial pathway-mediated apoptosis during MIRI, potentially through blockade of the Akt/ASK-1/p38 MAPK pathway [155] . The natural antioxidant Salvianolic Acid B (SAB) protects cardiomyocytes by downregulating JNK phosphorylation and modulating the Bax/Bcl-2 ratio and caspase-3 expression [156] . Luteolin, a flavonoid widely distributed in plants, exhibits diverse biological activities, including antimicrobial [157] , antioxidant [22] , and anticancer effects [158] . Research has demonstrated that Luteolin inhibits the ROS-activated MAPK signaling pathway, displaying substantial antioxidant efficacy [159] . This compound ameliorates impaired mitochondrial morphology and protects against MIRI by regulating the MAPK pathway [159] . Furthermore, Luteolin mitigates MIRI-induced cellular damage and histopathological changes by improving mitochondrial function, promoting anti-apoptotic effects, and modulating autophagy [160] . Its specific protective mechanisms likely involve regulation of JNK and p38 MAPK signaling pathways [161] . Additionally, Leonurine (4-guanidino-n-butyl syringate), an alkaloid derived from Herbaleonuri, has been identified as having cardioprotective properties. Studies suggest that its mechanism of action involves reducing ROS levels, modulating Akt phosphorylation, and concurrently decreasing the phosphorylation of p38 and JNK [162] . Table 7 Compounds Inhibiting the MAPK Signaling Pathway All-trans Retinoic Acid MAPK signalling pathway RORC, HTR2B, RARA, RXRA, ADORA3… [154] Hirsutine MAPK signalling pathway BCHE, OPRD1, ADRA2A, ADRA2C, ADRA2B… [155] Salvianolic acid B MAPK signalling pathway CA7, CA12, CA4, AKR1B1, MMP9… [156] Luteolin MAPK signalling pathway NOX4, AKR1B1, CDK5R1, XDH, MAOA… [159] Leonurine MAPK signalling pathway SLC29A1, PLAU, HGFAC, PLAT, F7… [162] 5 Dual-mechanism antioxidants in mitigating MIRI Compared to conventional single-mechanism antioxidants, dual-mechanism antioxidants offer enhanced therapeutic potential by not only directly neutralizing ROS but also activating endogenous antioxidant pathways, thereby providing synergistic protection against MIRI [19] . Consequently, they often demonstrate more comprehensive therapeutic efficacy in addressing the multifaceted and multi-pathway complexities of MIRI (Table 8). Lazaroid compounds represent a novel class of antioxidant agents with potent ROS-scavenging capabilities [163] . The derivative U83836, which incorporates a functional group from Vitamin E, exhibits enhanced antioxidant activity. Studies show that U83836 reduces MDA content and creatine kinase activity in cardiomyocytes while elevating SOD and GSH-Px activities, offering significant protection to rat hearts following ischemia-reperfusion [164] . Notably, protein kinase C (PKC) inhibitors attenuate the cardioprotective effects of U83836, suggesting that its mechanism involves both direct ROS scavenging and modulation of the PKC signaling pathway [164] . This dual action—combining direct ROS scavenging with signal pathway modulation—enables U83836 to maintain cellular homeostasis more effectively than simple free radical scavengers. Hydralazine, developed in 1951 as a vasodilator for hypertension and heart failure management [165, 166] , has shown protective effects in renal ischemia-reperfusion injury models [167] , although its impact on cardiac I/R injury remained unclear. Chengzong Li et al. confirmed that hydralazine alleviates MIRI in rats by activating the PI3K/Akt signaling pathway, inhibiting endothelial nitric oxide synthase (eNOS) phosphorylation, and directly reacting with ROS [168] . This indicates that the dual properties of direct antioxidant activity and PI3K/Akt pathway activation contribute to hydralazine’s enhanced cardioprotective effects in MIRI. Melatonin, a neuroendocrine hormone that regulates circadian rhythms, mood, immunity, and reproductive functions [169, 170] , also exhibits potent free radical-scavenging activity, making it valuable in anti-aging and anti-cancer applications [171] . Melatonin directly neutralizes highly reactive radicals, such as ·OH, peroxyl radicals, and peroxynitrite (ONOO – ), through addition reactions, forming stable products that help maintain intracellular homeostasis [172] . Additionally, melatonin upregulates the PGC-1α/Nrf2 signaling pathway, reducing oxidative stress and inflammatory responses following ischemia-reperfusion [172] . A complex interplay exists between ROS and the NLRP3 inflammasome, where ROS can activate NLRP3, and NLRP3 inhibitors can alleviate oxidative stress and inflammation [173] , demonstrating protective effects in mouse MIRI models [174] . Shurong Li et al. reported that melatonin reduces cardiomyocyte damage by inhibiting NLRP3 inflammasome activation, likely linked to its ability to lower ROS levels [175] . Melatonin exemplifies a dual-mechanism—or even multi-mechanism—synergy, constructing a multi-dimensional protective network across various pathways. Its comprehensive protection in MIRI models supports its investigation in multiple clinical trials. In addition to scavenging ROS [30] , vitamin C promotes the dissociation of the Keap1-Nrf2 complex, driving Nrf2 nuclear translocation and upregulating the expression of antioxidant proteins such as HO-1, thereby enhancing the cell’s endogenous antioxidant capacity [32-34] . Concurrently, vitamin C activates the PI3K/Akt pathway, a central pro-survival axis, inhibiting mitochondrial-mediated apoptosis by enhancing Akt/GSK-3β phosphorylation [35, 36] . It also suppresses the excessive activation of the p38 and JNK MAPK stress pathways triggered by ROS, thereby blocking pro-apoptotic signal transduction [37-39] , and may improve myocardial energy metabolism through the AMPK pathway [40] . The combination of direct scavenging and multi-pathway systemic regulation results in a protective efficacy that far surpasses that of single-action antioxidant vitamins. Honokiol exemplifies the unique advantage of natural products by integrating multi-target and multi-effect actions. In addition to directly scavenging ROS [57] , it activates SIRT1, which promotes the nuclear translocation and transcriptional activity of Nrf2, forming a key axis for enhancing antioxidant defense [58] . Simultaneously, Honokiol activates the PI3K/Akt pathway, effectively inhibiting mitochondrial apoptosis [59] . Notably, it can also mitigate myocardial hypertrophy and fibrosis while promoting protective autophagy in pathological models by modulating AMPK, a central hub for cellular energy metabolism and autophagy [60, 61] . By regulating these multiple signaling pathways, Honokiol integrates antioxidant, anti-apoptotic, and anti-inflammatory effects, highlighting the distinctive advantage of multi-target natural products in intervening in complex pathological processes. In summary, the fundamental advantage of dual-mechanism antioxidants over single-mechanism agents lies in their synergistic execution of both direct scavenging and endogenous regulatory functions. They not only neutralize ROS but also enhance the cell’s defensive and reparative capabilities across multiple dimensions by modulating key signaling pathways such as Nrf2 and PI3K/Akt. This multi-target, multi-level intervention against the complex pathological network of MIRI provides a more promising strategy for achieving efficient myocardial protection and offers a clear direction for future drug development. Table 8 Compounds with Dual Mechanisms of Action U83836 PKC signalling pathway HTR2B, FYN, DRD2, HTR2C, HRH1… [164] Hydralazine PI3K/Akt CA2, CA9, PARP1, GSK3B, METAP1… [168] Melatonin PGC‑1α/Nrf2、NLRP3 MTNR1A, MTNR1B, NQO2, HTR2B, HTR2A… [172, 175] Vitamin C Nrf2/PI3K-Akt/MAPK/AMPK GSK3B [31-40] Honokiol Nrf2/PI3K-Akt/AMPK ALOX5, CNR1, CNR2, CA2, BRAF… [58-61] 6 Mitigation of MIRI by suppressing ferroptosis Ferroptosis, a recently identified form of regulated cell death in MIRI, is characterized by iron-dependent lipid peroxidation, although its precise molecular mechanisms remain incompletely understood [176] . Accumulating evidence highlights a close pathophysiological connection between ROS and ferroptosis during MIRI progression [177, 178] , establishing the modulation of this process as a promising therapeutic strategy. Several studies have shown that various compounds can exert cardioprotective effects by modulating pathways associated with ferroptosis. Tie Hu et al. demonstrated that pretreatment with epigallocatechin-3-gallate (EGCG) alleviates MIRI by upregulating 14-3-3η protein expression, while simultaneously reducing ferroptosis-related markers and ROS levels [179] . In subsequent research, the same team found that activating peroxisome proliferator-activated receptor α (PPAR-α) effectively suppressed MIRI-induced ferroptosis by lowering MDA, total iron, and ROS levels [180] . Additionally, (-)-Epicatechin (EPI) has been shown to protect against MIRI by promoting the expression of the deubiquitinating enzyme USP14, reducing autophagy levels, inhibiting autophagy-dependent ferroptosis, and mitigating oxidative stress [181] . Zhenhua Wu et al. indicated that metformin significantly alleviates ferroptosis in MIRI, an effect likely linked to its ability to reduce ROS levels [182] . Another medicinal natural product, hederagenin (HDG), has also been identified as an inhibitor of ferroptosis. Li Zhao et al. demonstrated that HDG alleviates oxidative stress in both in vivo and in vitro models by reducing ROS generation and maintaining a balance between antioxidant and pro-oxidant enzymes [183] . Simultaneously, HDG significantly suppressed ferroptosis induced by MIRI, as evidenced by decreased lipid peroxidation levels and reduced intracellular iron content [183] . In summary, ferroptosis represents an important pathological mechanism in MIRI, engaging in a complex interactive network with oxidative stress. A deeper understanding of the specific regulatory mechanisms linking ROS and ferroptosis will provide key directions for developing novel therapeutic strategies against MIRI. 7 Nanosystems Conventional antioxidant therapies for MIRI often face limitations in clinical efficacy due to suboptimal pharmacokinetic properties, low bioavailability, poor stability, and potential side effects [184] . Recent advancements in nanotechnology have provided innovative solutions to overcome these challenges, enabling targeted drug delivery [185] controlled release, and multifunctional integration [186] . Nanocarrier-based antioxidant drug delivery systems hold promise for integrating multiple therapeutic advantages, offering comprehensive strategies for alleviating MIRI and demonstrating broad application prospects [187] . Recent research illustrates how various nanosystem designs can address key limitations of conventional antioxidants, such as solubility, targeting, and microenvironment modulation, significantly enhancing their therapeutic efficacy against MIRI. Multiple nanotechnology-based antioxidant strategies have been developed, yielding remarkable effects in mitigating MIRI. Despite the potential of Baicalin (BAN) for MIRI treatment, its poor solubility and biocompatibility have limited its clinical application. To address this, Changgong Chen’s team developed a BAN-loaded nanodrug system using polydopamine (PDA)-modified Zeolitic imidazolate framework-8 (ZIF-8) as a carrier, named PZB NPs [188] . This system achieved a drug loading efficiency of 26.43% ± 1.55%, a hydrated particle size of approximately 102 nm, and demonstrated slow, sustained drug release in an acidic environment [188] . In vitro experiments confirmed that PZB NPs were non-cytotoxic, significantly enhancing the viability of H9c2 cells subjected to hypoxia/reoxygenation injury. The PZB NPs exerted protective effects by inhibiting apoptosis, scavenging ROS, and activating the Nrf2/HO-1 signaling pathway [188] . Further animal studies demonstrated that PZB NPs significantly reduced myocardial infarct size, improved cardiac fibrosis, and enhanced cardiac function in rats [188] . This nanocomposite carrier effectively overcame BAN’s inherent drawbacks of poor solubility and bioavailability, enabling efficient drug delivery and synergistic antioxidant activity, providing critical support for its future clinical translation [188] . Similarly, Ginsenoside Rg3, a potent antioxidant, suffers from high hydrophobicity and previously unclear molecular targets, limiting its application [189] . Lan Li et al. developed ROS-responsive nanoparticles (PEG-b-PPS) through self-assembly of poly(ethylene glycol) (PEG) and poly(propylene sulfide) (PPS) diblock copolymers for the loading and delivery of Rg3 [190] . Using molecular docking and gene silencing techniques, the study identified FoxO3a as a therapeutic target for Rg3. In a rat MIRI model, intramyocardial injection of Rg3-loaded PEG-b-PPS nanoparticles improved cardiac function and reduced infarct size. This strategy not only overcame the delivery challenge of hydrophobic drugs using nanoparticles but also elucidated its molecular target, FoxO3a, which inhibits oxidative stress and inflammation, offering an effective approach for treating ischemic diseases and advancing the clinical application of hydrophobic natural products [190] . In another innovative strategy, Nan Li et al. constructed NO/H 2 S-powered nanomotors to enhance the targeting of recombinant granulocyte colony-stimulating factor (G-CSF) [191] . These nanomotors actively chemotax toward injury sites with high ROS and inducible NOS (iNOS) expression, modulating the local microenvironment through the synergistic action of gas molecules [191] . This active drug delivery system surpasses traditional passive targeting methods by enhancing therapeutic efficacy while avoiding the potential toxicity associated with single-gas therapy [191] . To synergistically utilize the protective effects of nitric oxide (NO) and prevent its oxidation by ROS, researchers designed L-arginine-loaded selenium-coated gold nanocages, further modified with the cardiomyocyte-targeting peptide PCM to create AASP [192] . This system targets cardiomyocytes, improves mitochondrial function, blocks ROS generation, prevents NO oxidation, and regulates the mPTP to prevent further ROS release [192] . This nanosystem cleverly integrates targeted delivery, mitochondrial protection, and NO signaling regulation, exemplifying a sophisticated multi-mechanistic approach for combating MIRI [192] . To develop biomimetic therapeutic agents that combine catalytic ROS scavenging with anti-inflammatory functions, the teams of Kaiyan Xiang and Tianbao Ye synthesized a bimetallic nanozyme (Cu-TCPP-Mn) and a single-atom nanozyme (PtsaN-C), respectively [184, 193] . These nanozymes neutralize ROS and mitigate inflammation by mimicking the SOD/CAT cascade reaction and utilizing the efficient catalytic properties of single-atom centers [184, 193] . As a new generation of nanomaterials, these nanozymes exhibit intrinsic therapeutic activity without requiring traditional drug loading, offering high efficiency and stability, which provides innovative tools for sustained antioxidant therapy [184, 193] . To ensure long-term local retention and action of antioxidants at the injury site, Yang Zhu’s team developed a thermally responsive injectable hydrogel incorporating recyclable TEMPO radicals into the polymer backbone [194] . This hydrogel can diffuse through, integrate with, and remain in the infarcted myocardium for over a week, effectively preserving left ventricular geometry [194] . By addressing issues such as imprecise localization and short retention time seen with systemic administration, this thermally responsive hydrogel possesses the ideal characteristics for local application to soft tissues where ROS-mediated oxidative damage is a key pathological mechanism [194] . In summary, nanosystems, ranging from those that improve drug physicochemical properties and enable active/targeted delivery to those designed for stimulus-responsive release, integrating multiple therapeutic functions, and developing intrinsically active nanocatalysts and long-acting local formulations, clearly demonstrate the immense potential and diverse pathways of nanotechnology. These systems enhance the precision, efficacy, and safety of antioxidant therapy for MIRI, with future research expected to further advance these strategies toward clinical translation. 8 Target analysis Building upon the systematic review of compounds that alleviate MIRI through various strategies, such as direct ROS scavenging, regulation of antioxidant signaling pathways, inhibition of ferroptosis, and application of nanotechnology, this study conducted an integrated target analysis to elucidate the common mechanisms of action of these antioxidant drugs at a systems level. In this work, the SwissTargetPrediction online tool (https://www.swisstargetprediction.ch/) was employed to systematically predict the potential protein targets of all compounds discussed. The prediction identified 743 potential target proteins. By integrating authoritative databases like GeneCards and GenBank, 1,432 genes associated with MIRI and 1,999 genes related to ROS were identified. The intersection of these three datasets revealed 174 key genes that are potentially modulated by these compounds during the ROS-associated MIRI process (Fig. 1A). An interaction network was constructed between the compounds and these 174 key genes to further explore their potential functional relationships. Network analysis (Fig. 1B) revealed that node color intensity corresponds to the strength of the association. Within this network, a group of 16 agents, represented by Honokiol, demonstrated a broad influence across multiple genes. These multi-target agents appear to utilize key hub genes, such as ITGB1 and AKT1, as critical anchors, ensuring that their therapeutic impact extends to genes involved in both oxidative stress and inflammatory responses. This pattern suggests their cardioprotective effect may stem from the synergistic modulation of the core MIRI pathway linking oxidative stress to inflammation. In contrast, agents like Amifostine engage with fewer targets, primarily addressing either oxidative stress or inflammation as isolated pathological facets, which may translate to efficacy against specific symptoms but not the integrated disease state. Therefore, for complex pathologies like MIRI, which are characterized by a loss of functional homeostasis, employing multi-target agents that act on densely connected nodes within the network is more likely to enhance therapeutic efficacy and mitigate the risk of drug resistance. Consequently, network pharmacology provides a rational approach for the screening or de novo design of multi-target drug candidates capable of precisely targeting specific disease modules. This integrated target analysis not only supports the mechanisms of action of the various compound categories discussed but also reveals the intrinsic connections between different antioxidant strategies from a systems perspective. Consequently, it provides a solid theoretical foundation for multi-target drug design and combination therapy strategies. Figure 1 Protein-protein interaction (PPI) network analysis. 9 Clinical trials of antioxidants As the role of antioxidants in MIRI continues to be elucidated, numerous clinical trials investigating antioxidants for mitigating MIRI and providing myocardial protection have been registered through the National Center for Biotechnology Information (https://www.ncbi.nlm.nih.gov/). These studies aim to evaluate the safety and efficacy of various antioxidant drugs in humans, marking significant strides in translating basic research findings into clinical practice (Table 9). Among clinical treatments for MIRI, direct-acting free radical scavengers show promising translational potential. Edaravone, a clinically utilized free radical scavenger, has demonstrated improved outcomes for patients with acute myocardial infarction in its Phase IV clinical trial (NCT00265239). N-Acetylcysteine, by providing substrates for GSH synthesis, has shown regulatory effects on oxidative stress in multiple clinical trials (NCT06850831). Vitamin C, a classic antioxidant vitamin, has also been evaluated for its protective effects under high oxidative stress conditions through several clinical programs (NCT03509662). Although a clinical trial (NCT02762331) investigating the effects of high-dose vitamin C on inflammation in cardiac surgery patients was terminated due to insufficient efficacy, larger-scale studies have validated its effectiveness. Naturally sourced antioxidants have attracted significant attention due to their multi-target properties and favorable safety profiles. Melatonin has demonstrated a unique dual-protection mechanism by directly neutralizing free radicals while activating endogenous intracellular antioxidant systems. Relevant clinical trials (NCT01172171) cover various scenarios, including acute myocardial infarction and cardiac surgery. Notably, one trial (NCT00640094) was terminated due to commercial and strategic decisions rather than safety or efficacy concerns. Curcumin and Shenfu injection, representing traditional medicines, have provided preliminary evidence for the cardioprotective effects of natural products through clinical studies (NCT01528514, NCT02709798). Antioxidant strategies targeting the endogenous antioxidant system may represent a future direction. Sodium Nitrite, which converts to NO in vivo , improves microcirculation and alleviates oxidative damage. Its efficacy in acute myocardial infarction has been assessed in multiple clinical trials (NCT01388504). In addition to its glucose-lowering properties, Metformin regulates cellular energy metabolism and oxidative stress through the AMPK pathway, with clinical studies providing new evidence for its cardioprotective effects. Agents such as L-Glutamine (NCT04560309) and L-Carnitine (NCT06564909), which indirectly influence redox balance by maintaining metabolic homeostasis, have also entered clinical evaluation. Ethyl pyruvate, which elevates myocardial adenosine triphosphate (ATP) levels, mitigates myocardial oxidative damage, and reduces infarct size, was evaluated in a clinical trial (NCT00107666) that was eventually terminated due to slow patient recruitment. Clinical trials of novel targeted antioxidants offer promising prospects. PC-SOD (NCT03995732) enhances stability and targeting capability through modification of the natural enzyme. Elamipretide, a mitochondria-specific antioxidant, directly addresses ROS generation at its source, with its Phase II study (NCT01572909) completed. Doxycycline, investigated in coronary artery bypass graft surgery (NCT00246740), suggests antioxidant effects beyond its antibacterial properties. Arginine hemoglobin (NCT02314780) activates the endogenous defense system by inducing HO-1 expression, providing clinical support for this strategy. Overall, Edaravone, with its potent free radical scavenging capacity, and melatonin, which combines direct and indirect antioxidant actions, have shown promising clinical potential in improving myocardial injury markers and outcomes. These results highlight the clinical relevance of their mechanisms. However, challenges persist, as some clinical trials report insufficient efficacy, with several studies terminated due to failure to meet primary endpoints or commercial considerations. These setbacks highlight the multifaceted challenges faced by antioxidant therapy within the complex human environment. Key issues include patient population heterogeneity, individual variability in oxidative stress injury, the impact of dosing timing and routes, and the limitations of using antioxidants as standalone therapies within MIRI’s multi-pathway pathogenesis. Future research should prioritize precise patient stratification, optimization of administration regimens, and the integration of antioxidant therapies with reperfusion strategies to achieve significant breakthroughs in MIRI treatment. Table 9 Clinical Trials of Antioxidant Drugs for MIRI and Myocardial Protection Edaravone PHASE4 COMPLETED NCT00265239 N-Acetylcysteine PHASE2 NOT_YET_RECRUITING NCT06850831 PHASE1 COMPLETED NCT00237614 PHASE4 COMPLETED NCTO1501110 Vitamin C PHASE2 COMPLETED NCT03509662 PHASE1 TERMINATED NCT02762331 Melatonin PHASE2 COMPLETED NCT01172171 NA UNKNOWN NCT03303378 NA UNKNOWN NCT05552586 PHASE2 TERMINATED NCT00640094 Curcumin NA COMPLETED NCT01528514 Shenfu Injection PHASE4 COMPLETED NCT02709798 Sodium Nitrite PHASE2|PHASE3 COMPLETED NCT01388504 PHASE2 COMPLETED NCT00924118 PHASE2 COMPLETED NCT01584453 Metformin PHASE3 UNKNOWN NCT05708053 L-Glutamine NA UNKNOWN NCT03341169 PHASE3 COMPLETED NCT04560309 L-Carnitine PHASE2 RECRUITING NCT06564909 PC-SOD PHASE2 UNKNOWN NCT03995732 Elamipretide (MTP-131) PHASE2 COMPLETED NCT01572909 CTI-01 (Ethyl Pyruvate) PHASE2 TERMINATED NCT00107666 N-Hydroxy-Nor-Arginine PHASE1 COMPLETED NCT02009527 Doxycycline PHASE2 COMPLETED NCT00246740 Arginine Hemoglobin PHASE2 COMPLETED NCT02314780 10 Conclusions and perspectives Preventing and treating MIRI remains a critical challenge in the cardiovascular field, with urgent need for breakthroughs. This review systematically summarizes recent advancements in pharmaceutical strategies targeting MIRI through antioxidant mechanisms. The shift from traditional free radical scavengers to innovative nanoscale targeting systems, especially dual-mechanism agents that combine direct ROS scavenging with pathway regulation, reflects a growing understanding of the complex pathophysiological network underlying MIRI. Mechanistically, research has moved beyond simply neutralizing ROS to comprehensively regulate endogenous cellular defense systems. Activation of key signaling pathways, such as Nrf2 and PI3K/Akt, not only enhances the expression of antioxidant proteins like HO-1 and SOD but also inhibits multiple injury processes, including inflammation and apoptosis, providing multifaceted myocardial protection. Agents like vitamin C and Honokiol further exemplify the protective potential of regulating multiple pathways simultaneously, establishing a network-like protective effect. Notably, dual-mechanism antioxidants—those capable of both direct ROS scavenging and modulating endogenous antioxidant pathways—demonstrate superior efficacy compared to single-mechanism drugs in preclinical studies. These agents hold great promise as candidates for the development of a new generation of therapeutics. Moreover, the identification of novel regulated cell death pathways, such as ferroptosis, has broadened our understanding of ROS and MIRI, positioning related inhibitors as a new frontier in research (Fig. 2). Figure 2 Mechanisms of antioxidant pathways in attenuating MIRI. Recent advancements in nanomedicine have significantly enhanced the precision and effectiveness of antioxidant therapies. The development of ROS-responsive, cardiac-targeting nanocarriers has optimized drug biodistribution, retention, and on-demand release, improving therapeutic outcomes while minimizing systemic side effects. Case studies involving nano-engineered drugs like Ginsenoside Rg3 and BAN demonstrate the ability of nanotechnology to overcome two major limitations of conventional antioxidants: poor site-specific accumulation and short duration of action. However, translating promising preclinical findings into clinical practice remains a significant challenge. Issues such as the compositional complexity and undefined pharmacokinetics of natural products, along with the termination of certain clinical trials due to unclear efficacy or recruitment difficulties, highlight the need for more carefully considered translational pathways. Future research should prioritize the development of advanced nano-delivery platforms capable of precise temporal, spatial, and dosage control. Additionally, the rational design or combination of multi-target agents based on the principles of dual-mechanism strategies is essential. Additionally, identification and validation of biomarkers that accurately reflect myocardial oxidative damage and repair processes are critical for assessing clinical efficacy. Moreover, the efficacy of antioxidants is closely linked to their molecular structural features. Electron-donating groups, such as phenolic hydroxyls, facilitate direct ROS neutralization, while specific polar groups may enhance interactions with target proteins. These insights provide a critical theoretical foundation for optimizing the structure of next-generation antioxidants, particularly multi-target molecules that integrate both scavenging and regulatory functions. In conclusion, antioxidant-based therapeutic strategies for MIRI show great promise, particularly through multi-mechanism synergistic interventions, advanced intelligent delivery systems, and more refined clinical translation approaches. The integration of multidisciplinary expertise and closer collaboration between basic research and clinical application will be key to driving progress in this field, ultimately offering new, effective solutions for the clinical prevention and treatment of cardiovascular diseases. Acknowledgments We thank Bullet Edits Limited for the linguistic editing and proofreading of the manuscript. We thank Dr. Yang Jin for his contribution to the diagram in our manuscript. Data availability statement The original contributions presented in the study are included in the article material. Further inquiries can be directed to the corresponding author. Conflict of Interest The authors declare that no conflicts of interest in this work. Author Contributions All authors made substantial contributions to conception and design, acquisition of data, made diagrams, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to take responsibility and be accountable for all aspects of the work. Funding This work was supported by the Scientific and Technological Research Program of Chongqing Municipal Educatin Commission (KJQN202303604); Research Projects of Chongqing Industry & Trade Polytechnic (ZR202304). References 1 Li X, Ou W, Xie M, Yang J, Li Q, Li T. Nanomedicine‐Based Therapeutics for Myocardial Ischemic/Reperfusion Injury. Advanced Healthcare Materials 2023; 12.2 Kulek AR, Anzell A, Wider JM, Sanderson TH, Przyklenk K. Mitochondrial Quality Control: Role in Cardiac Models of Lethal Ischemia-Reperfusion Injury. Cells 2020; 9: 214.3 Matsushima S, Sadoshima J. Yin and Yang of NADPH Oxidases in Myocardial Ischemia-Reperfusion. Antioxidants 2022; 11: 1069.4 Albano GD, Gagliardo RP, Montalbano AM, Profita M. Overview of the Mechanisms of Oxidative Stress: Impact in Inflammation of the Airway Diseases. Antioxidants (Basel) 2022; 11.5 Jomova K, Alomar SY, Alwasel SH, Nepovimova E, Kuca K, Valko M. Several lines of antioxidant defense against oxidative stress: antioxidant enzymes, nanomaterials with multiple enzyme-mimicking activities, and low-molecular-weight antioxidants. Arch Toxicol 2024; 98: 1323-67.6 Gong G, Wan W, Zhang X, Chen X, Yin J. Management of ROS and Regulatory Cell Death in Myocardial Ischemia–Reperfusion Injury. Molecular Biotechnology 2024.7 Hensley K, Floyd RA. Reactive Oxygen Species and Protein Oxidation in Aging: A Look Back, A Look Ahead. Archives of Biochemistry and Biophysics 2002; 397: 377-83.8 Marian Valko, Mario Izakovic, Milan Mazur, Christopher J Rhodes, Telser J. Role of oxygen radicals in DNA damage and cancer incidence. Molecular and Cellular Biochemistry 2004; 266: 37-56.9 Murphy Michael P. How mitochondria produce reactive oxygen species. Biochemical Journal 2008; 417: 1-13.10 Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chemico-Biological Interactions 2006; 160: 1-40.11 Kylie M Venardos, Anthony Perkins, John Headrick, Kaye DM. Myocardial ischemia-reperfusion injury, antioxidant enzyme systems, and selenium: a review. Current Medicinal Chemistry 2007; 14: 1539-49.12 Trend S, Fonceca AM, Ditcham WG, Kicic A, Cf A. The potential of phage therapy in cystic fibrosis: Essential human-bacterial-phage interactions and delivery considerations for use in Pseudomonas aeruginosa-infected airways. Journal of Cystic Fibrosis 2017; 16: 663-70.13 Gjumrakch Aliev, Mark E Obrenovich, V Prakash Reddy, Justin C Shenk, Paula I Moreira, Akihiko Nunomura , et al . Antioxidant therapy in Alzheimer’s disease: theory and practice. Mini-reviews In Medicinal Chemistry 2008; 8: 1395-406.14 Heo J, Han S, Lee S. Free radicals as triggers of brain edema formation after stroke. Free Radical Biology and Medicine 2005; 39: 51-70.15 Hill MF. Emerging role for antioxidant therapy in protection against diabetic cardiac complications: experimental and clinical evidence for utilization of classic and new antioxidants. Current Cardiology Reports 2008; 4: 259-68.16 Lu X, Xie Q, Pan X, Zhang R, Zhang X, Peng G , et al . Type 2 diabetes mellitus in adults: pathogenesis, prevention and therapy. Signal Transduction and Targeted Therapy 2024; 9.17 Riccieri V, Spadaro A, Fuksa L, Firuzi O, Saso L, Valesini G. Specific oxidative stress parameters differently correlate with nailfold capillaroscopy changes and organ involvement in systemic sclerosis. Clinical Rheumatology 2007; 27: 225-30.18 Orellana-Urzúa S, Briones-Valdivieso C, Chichiarelli S, Saso L, Rodrigo R. Potential Role of Natural Antioxidants in Countering Reperfusion Injury in Acute Myocardial Infarction and Ischemic Stroke. Antioxidants 2023; 12: 1760.19 Wang J, Huang L, Cheng C, Li G, Xie J, Shen M , et al . Design, synthesis and biological evaluation of chalcone analogues with novel dual antioxidant mechanisms as potential anti-ischemic stroke agents. Acta Pharmaceutica Sinica B 2019; 9: 335-50.20 Zhu M, Wang J, Xie J, Chen L, Wei X, Jiang X , et al . Design, synthesis, and evaluation of chalcone analogues incorporate α,β-Unsaturated ketone functionality as anti-lung cancer agents via evoking ROS to induce pyroptosis. European Journal of Medicinal Chemistry 2018; 157: 1395-405.21 Wang L, Qiu S, Li X, Zhang Y, Huo M, Shi J. Myocardial‐Targeting Tannic Cerium Nanocatalyst Attenuates Ischemia/Reperfusion Injury. Angewandte Chemie International Edition 2023; 62: e202305576.22 Gu J, Zhang P, Li H, Wang Y, Huang Y, Fan L , et al . Cerium-Luteolin Nanocomplexes in Managing Inflammation-Related Diseases by Antioxidant and Immunoregulation. ACS Nano 2024; 18: 6229-42.23 Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ , et al . Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell 2017; 171: 273-85.24 Luangpraditkun K, Tissot M, Joompang A, Charoensit P, Grandmottet F, Viyoch J , et al . Prevention by the Natural Artocarpin of Morphological and Biochemical Alterations on UVB‐Induced HaCaT Cells. Oxidative Medicine and Cellular Longevity 2021; 2021.25 Seo M, Kim H, Lee JH, Park J-W. Pelargonidin ameliorates acetaminophen-induced hepatotoxicity in mice by inhibiting the ROS-induced inflammatory apoptotic response. Biochimie 2020; 168: 10-6.26 Wang W, Kang PM. Oxidative Stress and Antioxidant Treatments in Cardiovascular Diseases. Antioxidants 2020; 9: 1292.27 Dimas A, Politi A, Bargiota A, Panoskaltsis T, Vlahos NF, Valsamakis G. The Gestational Effects of Maternal Bone Marker Molecules on Fetal Growth, Metabolism and Long-Term Metabolic Health: A Systematic Review. International Journal of Molecular Sciences 2022; 23.28 Knuth MM, Xue J, Elnagheeb M, Gharaibeh RZ, Schoenrock SA, McRitchie S , et al . Early life exposure to vitamin D deficiency impairs molecular mechanisms that regulate liver cholesterol biosynthesis, energy metabolism, inflammation, and detoxification. Frontiers in Endocrinology 2024; 15.29 Zheng H, Xu Y, Liehn EA, Rusu M. Vitamin C as Scavenger of Reactive Oxygen Species during Healing after Myocardial Infarction. International Journal of Molecular Sciences 2024; 25.30 Zhang P, Zang M, Sang Z, Wei Y, Yan Y, Bian X , et al . Vitamin C alleviates LPS-induced myocardial injury by inhibiting pyroptosis via the ROS-AKT/mTOR signalling pathway. BMC Cardiovascular Disorders 2022; 22.31 Yang G, Zhou W, Zhang M, Zhong X, Qiu H, Xiang Y , et al . Induced oxidative stress and apoptosis by 1-bromopropane in SH-SY5Y cells correlates with inhibition of Nrf2 function. Drug and Chemical Toxicology 2023; 47: 756-66.32 Labib H, Badr AM, Abdelgwad M, Abd El-Galil TI. Keap1/Nrf2 pathway in sodium fluoride-induced cardiac toxicity and the prophylactic role of vitamin C versus platelet-rich plasma. Folia Morphologica 2022; 81: 663-78.33 Sahu BD, Putcha UK, Kuncha M, Rachamalla SS, Sistla R. Carnosic acid promotes myocardial antioxidant response and prevents isoproterenol-induced myocardial oxidative stress and apoptosis in mice. Molecular and Cellular Biochemistry 2014; 394: 163-76.34 Rodrigo R, Prieto Juan C, Castillo R. Cardioprotection against ischaemia/reperfusion by vitamins C and E plus n−3 fatty acids: molecular mechanisms and potential clinical applications. Clinical Science 2012; 124: 1-15.35 Misra UK, Deedwania R, Pizzo SV. Activation and Cross-talk between Akt, NF-κB, and Unfolded Protein Response Signaling in 1-LN Prostate Cancer Cells Consequent to Ligation of Cell Surface-associated GRP78. Journal of Biological Chemistry 2006; 281: 13694-707.36 Hao J, Li W-W, Du H, Zhao Z-F, Liu F, Lu J-C , et al . Role of Vitamin C in Cardioprotection of Ischemia/Reperfusion Injury by Activation of Mitochondrial KATP Channel. Chemical and Pharmaceutical Bulletin 2016; 64: 548-57.37 Singla DK, Ludke A, Akolkar G, Ayyappan P, Sharma AK, Singal PK. Time course of changes in oxidative stress and stress-induced proteins in cardiomyocytes exposed to doxorubicin and prevention by vitamin C. Plos One 2017; 12.38 Eguchi M, Monden K, Miwa N. Role of MAPK phosphorylation in cytoprotection by pro‐vitamin C against oxidative stress‐induced injuries in cultured cardiomyoblasts and perfused rat heart. Journal of Cellular Biochemistry 2003; 90: 219-26.39 Xiao Y, Su C, Zhang G, Liang L, Jin T, Bradley J , et al . Vitamin C Improves the Outcomes of Cardiopulmonary Resuscitation and Alters Shedding of Syndecan‐1 and p38/MAPK Phosphorylation in a Rat Model. Journal of the American Heart Association 2022; 11.40 Wang HL, Cui XH, Yu HL, Wu R, Xu X, Gao JP. Synergistic effects of polydatin and vitamin C in inhibiting cardiotoxicity induced by doxorubicin in rats. Fundamental & Clinical Pharmacology 2017; 31: 280-91.41 Handley EL, Callanan A. Effects of electrospun fibers containing ascorbic acid on oxidative stress reduction for cardiac tissue engineering. Journal of Applied Polymer Science 2023; 140: e54242.42 Zhang J, Ren X, Nie Z, You Y, Zhu Y, Chen H , et al . Dual-responsive renal injury cells targeting nanoparticles for vitamin E delivery to treat ischemia reperfusion-induced acute kidney injury. Journal of Nanobiotechnology 2024; 22.43 Yinhong Chen, Grace Davis-Gorman, Ronald Ross Watson, McDonagh PF. Vitamin E attenuates myocardial ischemia-reperfusion injury in murine AIDS. Cardiovascular Toxicology 2002; 2: 119-27.44 Ma X, Xu S, Li J, Cui L, Dong J, Meng X , et al . Selenomethionine protected BMECs from inflammatory injury and oxidative damage induced by Klebsiella pneumoniae by inhibiting the NF-κB and activating the Nrf2 signaling pathway. International Immunopharmacology 2022; 110.45 Takamura T. Hepatokine Selenoprotein P-Mediated Reductive Stress Causes Resistance to Intracellular Signal Transduction. Antioxidants & Redox Signaling 2020; 33: 517-24.46 Xue Q, Lai H, Zhang H, Li G, Pi F, Wu Q , et al . Selenium Attenuates Radiation Colitis by Regulating cGAS‐STING Signaling. Advanced Science 2024.47 Diyabalanage S, Dangolla A, Mallawa C, Rajapakse S, Chandrajith R. Bioavailability of selenium (Se) in cattle population in Sri Lanka based on qualitative determination of glutathione peroxidase (GSH-Px) activities. Environmental Geochemistry and Health 2019; 42: 617-24.48 Zhang L, Gao Y, Feng H, Zou N, Wang K, Sun D. Effects of selenium deficiency and low protein intake on the apoptosis through a mitochondria-dependent pathway. J Trace Elem Med Biol 2019; 56: 21-30.49 Zhang F, Ye Z, Ran Y, Liu C, Zhang M, Xu X , et al . Ruthenium red alleviates post-resuscitation myocardial dysfunction by upregulating mitophagy through inhibition of USP33 in a cardiac arrest rat model. European Journal of Pharmacology 2024; 974: 176633.50 Zhang S, Zhang Y, Peng N, Zhang H, Yao J, Li Z , et al . Pharmacokinetics and Biodistribution of Zinc-Enriched Yeast in Rats. The Scientific World Journal 2014; 2014: 1-4.51 Akbari G. Role of Zinc Supplementation on Ischemia/Reperfusion Injury in Various Organs. Biological Trace Element Research 2019; 196: 1-9.52 Kang Y, Liu Z, Li W, Li X, Zhang X, Xu Z , et al . Anti-oxidative and anti-inflammatory activities of the ethanol extract of edible flower from Chimonanthus praecox. Frontiers in Pharmacology 2022; 13.53 Yuan X, Liu K, Dong P, Han H. Protective effect and mechanism of different proportions of “Danggui-Kushen” herb pair on ischemic heart disease. Heliyon 2023; 9: e22150.54 Li N, Liang Y, Zhang L, Xu C, Wang L. Neolignans in Magnolia officinalis as natural anti-Alzheimer’s disease agents: A systematic review. Ageing Research Reviews 2024; 99.55 Zhang Y, Zhang P, Zhang X, Liu Y. HH-A, a modified honokiol, protects against cerebral ischemia/reperfusion induced brain injury in rodent via Nrf2/HO-1 signaling pathways. Naunyn-Schmiedeberg’s Archives of Pharmacology 2023; 397: 3389-402.56 Zhang Z, Scanlan A, Koneru R, Morrell CR, Reece MD, Edwards E , et al . Honokiol hexafluoro confers reversal of neuropathological markers of HIV infection in a murine SCID model. Neurotherapeutics 2024; 21.57 Tan Z, Liu H, Song X, Ling Y, He S, Yan Y , et al . Honokiol post-treatment ameliorates myocardial ischemia/reperfusion injury by enhancing autophagic flux and reducing intracellular ROS production. Chemico-Biological Interactions 2019; 307: 82-90.58 Zhang B, Zhai M, Li B, Liu Z, Li K, Jiang L , et al . Honokiol Ameliorates Myocardial Ischemia/Reperfusion Injury in Type 1 Diabetic Rats by Reducing Oxidative Stress and Apoptosis through Activating the SIRT1‐Nrf2 Signaling Pathway. Oxidative Medicine and Cellular Longevity 2018; 2018.59 Lv L, Kong Q, Li Z, Zhang Y, Chen B, Lv L , et al . Honokiol Provides Cardioprotection from Myocardial Ischemia/Reperfusion Injury (MI/RI) by Inhibiting Mitochondrial Apoptosis via the PI3K/AKT Signaling Pathway. Cardiovascular Therapeutics 2022; 2022: 1-9.60 Lin X, Zhang H, Chu Y, Zhang Y, Xu C, Xie H , et al . Honokiol ameliorates angiotensin II‐induced cardiac hypertrophy by promoting dissociation of the Nur77–LKB1 complex and activating the AMPK pathway. Journal of Cellular and Molecular Medicine 2023; 28.61 Wei X-q, Zhang H-s, Wei G-h, Zhang J-g, Du Y-y, Tan H-y , et al . Honokiol Protects against Anti‐β1‐Adrenergic Receptor Autoantibody‐Induced Myocardial Dysfunction via Activation of Autophagy. Oxidative Medicine and Cellular Longevity 2018; 2018.62 Liang C, Ju W, Pei S, Tang Y, Xiao Y. Pharmacological Activities and Synthesis of Esculetin and Its Derivatives: A Mini-Review. Molecules 2017; 22: 387.63 Pullaiah CP, Nelson VK, Rayapu S, G VN, Kedam T. Exploring cardioprotective potential of esculetin against isoproterenol induced myocardial toxicity in rats: in vivo and in vitro evidence. BMC Pharmacol Toxicol 2021; 22: 43.64 Tan Y, Bao X, Li Y, Song G, Lu H, Sun X , et al . Colchicine Attenuates Microvascular Obstruction after Myocardial Ischemia-Reperfusion Injury by Inhibiting the Proliferation of Neutrophil in Bone Marrow. Cardiovascular Drugs and Therapy 2023.65 Xia B, Li Q, Wu J, Yuan X, Wang F, Lu X , et al . Sinomenine Confers Protection Against Myocardial Ischemia Reperfusion Injury by Preventing Oxidative Stress, Cellular Apoptosis, and Inflammation. Frontiers in Pharmacology 2022; 13.66 Li Q, Xia B, Wu J, Yuan X, Lu X, Huang C , et al . Indole-3-Carbinol (I3C) Protects the Heart From Ischemia/Reperfusion Injury by Inhibiting Oxidative Stress, Inflammation, and Cellular Apoptosis in Mice. Frontiers in Pharmacology 2022; 13.67 Ding J, Zhang S, Li Q, Xia B, Wu J, Lu X , et al . Geraniin attenuates isoproterenol-induced cardiac hypertrophy by inhibiting inflammation, oxidative stress and cellular apoptosis. The Korean Journal of Physiology & Pharmacology 2024; 29: 307-19.68 Yamashita T, Abe K. Update on Antioxidant Therapy with Edaravone: Expanding Applications in Neurodegenerative Diseases. International Journal of Molecular Sciences 2024; 25.69 Kikuchi K, Takeshige N, Miura N, Morimoto Y, Ito T, Tancharoen S , et al . Beyond free radical scavenging: Beneficial effects of edaravone (Radicut) in various diseases (Review). Experimental and Therapeutic Medicine 2012; 3: 3-8.70 Guoming Zhang, Yuanyuan Sun, Yu Wang, Xiaoyan Li, Tiande Li, Shaoping Su , et al . Local administration of lactic acid and a low dose of the free radical scavenger, edaravone, alleviates myocardial reperfusion injury in rats. Journal of Cardiovascular Pharmacology 2013; 62: 369-78.71 Kenichi Tsujita, Hideki Shimomura, Koichi Kaikita, Hiroaki Kawano, Jun Hokamaki, Yasuhiro Nagayoshi , et al . Long-term efficacy of edaravone in patients with acute myocardial infarction. Circulation Journal 2006; 70: 832-7.72 Bil-Lula I, Kuliczkowski W, Krzywonos-Zawadzka A, Frydrychowski P, Stygar D, Hałucha K , et al . Mixture of Doxycycline, ML-7 and L-NAME Restores the Pro- and Antioxidant Balance during Myocardial Infarction—In Vivo Pig Model Study. Biomedicines 2024; 12: 784.73 Graziano R, Nicolantonio DO. The role of selenium, zinc and antioxidant vitamin supplementation in the treatment of bronchial asthma: adjuvant therapy or not? Expert Opinion on Investigational Drugs 2005; 14: 1145-55.74 Rudnicki SA. Prevention and Treatment of Peripheral Neuropathy after Bariatric Surgery. Current Treatment Options in Neurology 2010; 12: 29-36.75 Jamieson CS, Misa J, Tang Y, Billingsley JM. Biosynthesis and synthetic biology of psychoactive natural products. Chemical Society Reviews 2021; 50: 6950-7008.76 Moon D-O. Targeting SHP2 with Natural Products: Exploring Saponin-Based Allosteric Inhibitors and Their Therapeutic Potential. Current Issues in Molecular Biology 2025; 47.77 Jeyachandran S, Sekar S. Natural Anti-Biofilm Agents: A Comprehensive Review and Future Perspectives. Current Microbiology 2025; 83.78 Wang C, Gu H, Huo X, Yuan B, Li S, Xu J , et al . Edaravone dexborneol versus placebo on functional outcomes in patients with acute ischaemic stroke undergoing endovascular thrombectomy (TASTE-2): randomised controlled trial. Bmj 2026; 392.79 Zhang S, Yan F, Luan F, Chai Y, Li N, Wang Y-W , et al . The pathological mechanisms and potential therapeutic drugs for myocardial ischemia reperfusion injury. Phytomedicine 2024; 129.80 Li Y, Luo Y, Wang J, Shi H, Liao J, Wang Y , et al . Discovery of novel danshensu derivatives bearing pyrazolone moiety as potential anti-ischemic stroke agents with antioxidant activity. Bioorganic Chemistry 2023; 131.81 Fridovich I. Superoxide radical and superoxide dismutases. Annual review of biochemistry 1995; 64: 97-112.82 Hou Y, Fan F, Xie N, Zhang Y, Wang X, Meng X. Rhodiola crenulata alleviates hypobaric hypoxia-induced brain injury by maintaining BBB integrity and balancing energy metabolism dysfunction. Phytomedicine 2024; 128.83 Zhu L, Wei T, Chang X, He H, Gao J, Wen Z , et al . Effects of Salidroside on Myocardial Injury In Vivo In Vitro via Regulation of Nox/NF-κB/AP1 Pathway. Inflammation 2015; 38: 1589-98.84 Wang Z, Qiang X, Peng Y, Fu W, Zhao Q, He D. Design and synthesis of salidroside analogs and their bioactivity against septic myocardial injury. Bioorganic Chemistry 2023; 138.85 Wang Z, Yu J, Wu J, Qi F, Wang H, Wang Z , et al . Scutellarin protects cardiomyocyte ischemia–reperfusion injury by reducing apoptosis and oxidative stress. Life Sciences 2016; 157: 200-7.86 Domingos AE, Seara FAC, Oliveira DF, Maciel L, Barbosa RAQ, Barcellos LC , et al . Mitochondrial dysfunction and cardiac ischemia/reperfusion injury are attenuated by nandrolone: Role of JAK-STAT3 pathway. Steroids 2023; 197: 109247.87 Xing N, Qin J, Ren D, Du Q, Li Y, Mi J , et al . Integrating UPLC-Q-Exactive Orbitrap/MS, network pharmacology and experimental validation to reveal the potential mechanism of Tibetan medicine Rhodiola granules in improving myocardial ischemia-reperfusion injury. Journal of Ethnopharmacology 2023; 314: 116572.88 Araujo AMd, Cerqueira SVSd, Menezes-Filho JERd, Heimfarth L, Matos KKdOG, Mota KO , et al . Naringin improves post-ischemic myocardial injury by activation of KATP channels. European Journal of Pharmacology 2023; 958: 176069.89 Cheng X, Liu Y, Qi B, Wang Y, Zheng Y, Liang X , et al . Glycyrrhizic acid alleviated MI/R-induced injuries by inhibiting Hippo/YAP signaling pathways. Cellular Signalling 2024; 115: 111036.90 Ding MY, Ning C, Chen SR, Yin HR, Xu J, Wang Y. Discovery of natural product derivative triptolidiol as a direct NLRP3 inhibitor by reducing K63-specific ubiquitination. Br J Pharmacol 2024.91 Bin Yang, Ping Yan, Guang-Zhao Yang, Hui-Li Cao, Fei Wang, Li B. Triptolide reduces ischemia/reperfusion injury in rats and H9C2 cells via inhibition of NF‑κB, ROS and the ERK1/2 pathway. International Journal of Molecular Medicine 2018; 41: 3127-36.92 Wadhwa S, Mumper RJ. D-penicillamine and other low molecular weight thiols: Review of anticancer effects and related mechanisms. Cancer Letters 2013; 337: 8-21.93 Wu S-z, Tao L-y, Wang J-n, Xu Z-q, Wang J, Xue Y-j , et al . Amifostine Pretreatment Attenuates Myocardial Ischemia/Reperfusion Injury by Inhibiting Apoptosis and Oxidative Stress. Oxidative Medicine and Cellular Longevity 2017; 2017: 4130824.94 Wu J, Wang J, Wang L, Huang Y. Topical retinoic acid induces corneal strengthening by upregulating transglutaminase 2 in murine cornea. Experimental Eye Research 2022; 214.95 Luyuan Tao, Kaiyu Huang, Jiaoni Wang, Yangjing Xue, Yingying Zhou, Fei He , et al . Retinol palmitate protects against myocardial ischemia/reperfusion injury via reducing oxidative stress and inhibiting apoptosis. American Journal of Translational Research 2019; 11: 1510-20.96 He W, Wang J, Jin Q, Zhang J, Liu Y, Jin Z , et al . Design, green synthesis, antioxidant activity screening, and evaluation of protective effect on cerebral ischemia reperfusion injury of novel monoenone monocarbonyl curcumin analogs. Bioorganic Chemistry 2021; 114: 105080.97 Peng S, Zhang B, Meng X, Yao J, Fang J. Synthesis of Piperlongumine Analogues and Discovery of Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Activators as Potential Neuroprotective Agents. Journal of Medicinal Chemistry 2015; 58: 5242-55.98 Roberta Gonnella, Roberta Santarelli, Antonella Farina, Marisa Granato, Gabriella D’Orazi, Alberto Faggioni , et al . Kaposi sarcoma associated herpesvirus (KSHV) induces AKT hyperphosphorylation, bortezomib-resistance and GLUT-1 plasma membrane exposure in THP-1 monocytic cell line. Journal of Experimental & Clinical Cancer Research 2013; 32: 79.99 Tang BL. RAB39B’s role in membrane traffic, autophagy, and associated neuropathology. Journal of Cellular Physiology 2020; 236: 1579-92.100 Zhao LX, Ge YH, Li JB, Xiong CH, Law PY, Xu JR , et al . M1 muscarinic receptors regulate the phosphorylation of AMPA receptor subunit GluA1via a signaling pathway linking cAMP‐PKA and PI3K‐Akt. The FASEB Journal 2019; 33: 6622-31.101 Zhou J, Chen C. Suppression of malignant melanoma by knocking down growth differentiation factor-15 via inhibiting PTEN/PI3K/AKT signaling pathway. Journal of Cancer 2024; 15: 1115-23.102 Yang S, Lee W, Lee B-S, Lee C, Park EK, Ku S-K , et al . Aloin Reduces HMGB1-Mediated Septic Responses and Improves Survival in Septic Mice by Activation of the SIRT1 and PI3K/Nrf2/HO-1 Signaling Axis. The American Journal of Chinese Medicine 2019; 47: 613-33.103 Xiaolong Chen, Junbin Zhang, Long Xia, Li Wang, Hui Li, Huilin Liu , et al . β-Arrestin-2 attenuates hepatic ischemia-reperfusion injury by activating PI3K/Akt signaling. Aging (Albany NY) 2020; 13: 2251-63.104 Teng H, Wu D, Lu L, Gao C, Wang H, Zhao Y , et al . Design and synthesis of 3,4-seco-lupane triterpene derivatives to resist myocardial ischemia-reperfusion injury by inhibiting oxidative stress-mediated mitochondrial dysfunction via the PI3K/AKT/HIF-1α axis. Biomedicine & Pharmacotherapy 2023; 167: 115452.105 Jiahui Zhu, Rong Ma, Li G. Drug repurposing: Clemastine fumarate and neurodegeneration. Biomedicine & Pharmacotherapy 2023; 157: 113904.106 Yuan X, Juan Z, Zhang R, Sun X, Yan R, Yue F , et al . Clemastine Fumarate Protects Against Myocardial Ischemia Reperfusion Injury by Activating the TLR4/PI3K/Akt Signaling Pathway. Frontiers in Pharmacology 2020; 11.107 Dong K, Xu W, Yang J, Qiao H, Wu L. Neuroprotective effects of Tanshinone IIA on permanent focal cerebral ischemia in mice. Phytotherapy Research 2008; 23: 608-13.108 Li Q, Shen L, Wang Z, Jiang H-P, Liu L-X. Tanshinone IIA protects against myocardial ischemia reperfusion injury by activating the PI3K/Akt/mTOR signaling pathway. Biomedicine & Pharmacotherapy 2016; 84: 106-14.109 Li M, Cui H, Deng H, Deng Y, Yin S, Li T , et al . Urolithin A promotes the degradation of TMSB10 to deformation F-actin in non-small-cell lung cancer. Phytomedicine 2024; 135.110 Kuerec AH, Lim XK, Khoo ALY, Sandalova E, Guan L, Feng L , et al . Targeting aging with urolithin A in humans: A systematic review. Ageing Research Reviews 2024; 100.111 Tang L, Mo Y, Li Y, Zhong Y, He S, Zhang Y , et al . Urolithin A alleviates myocardial ischemia/reperfusion injury via PI3K/Akt pathway. Biochemical and Biophysical Research Communications 2017; 486: 774-80.112 Huang C-Y, Lin Y-T, Kuo H-C, Chiou W-F, Lee M-H. Compounds isolated from Eriobotrya deflexa leaves protect against ultraviolet radiation B-induced photoaging in human fibroblasts. Journal of Photochemistry and Photobiology B: Biology 2017; 175: 244-53.113 da Rocha EV, Falchetti F, Pernomian L, de Mello MMB, Parente JM, Nogueira RC , et al . Quercetin decreases cardiac hypertrophic mediators and maladaptive coronary arterial remodeling in renovascular hypertensive rats without improving cardiac function. Naunyn-Schmiedeberg’s Archives of Pharmacology 2022; 396: 939-49.114 Wu J, Lv T, Liu Y, Liu Y, Han Y, Liu X , et al . The role of quercetin in NLRP3-associated inflammation. Inflammopharmacology 2024.115 Liu H, Guo X, Chu Y, Lu S. Heart protective effects and mechanism of quercetin preconditioning on anti-myocardial ischemia reperfusion (IR) injuries in rats. Gene 2014; 545: 149-55.116 Stępkowski TM, Kruszewski MK. Molecular cross-talk between the NRF2/KEAP1 signaling pathway, autophagy, and apoptosis. Free Radical Biology and Medicine 2011; 50: 1186-95.117 Ye P, Yang X-l, Chen X, Shi C. Hyperoside attenuates OVA-induced allergic airway inflammation by activating Nrf2. International Immunopharmacology 2017; 44: 168-73.118 Theodossiou TA, Olsen CE, Jonsson M, Kubin A, Hothersall JS, Berg K. The diverse roles of glutathione-associated cell resistance against hypericin photodynamic therapy. Redox Biology 2017; 12: 191-7.119 Hou J-Y, Liu Y, Liu L, Li X-M. Protective effect of hyperoside on cardiac ischemia reperfusion injury through inhibition of ER stress and activation of Nrf2 signaling. Asian Pacific Journal of Tropical Medicine 2016; 9: 76-80.120 Chunlei Zhang, Zhonghua Shi, Qinyi Xu, Jianqing He, Lei Chen, Zehua Lu , et al . Astragaloside IV alleviates stroke-triggered early brain injury by modulating neuroinflammation and ferroptosis via the Nrf2/HO-1 signaling pathway. Acta Cirurgica Brasileira 2023; 38: e380723.121 Wang J, Ke J, Wu X, Yan Y. Astragaloside prevents UV‐induced keratinocyte injury by regulating TLR4/NF‐κB pathway. Journal of Cosmetic Dermatology 2021; 21: 1163-70.122 Jiang M, Ni J, Cao Y, Xing X, Wu Q, Fan G. Astragaloside IV Attenuates Myocardial Ischemia-Reperfusion Injury from Oxidative Stress by Regulating Succinate, Lysophospholipid Metabolism, and ROS Scavenging System. Oxidative Medicine and Cellular Longevity 2019; 2019: 1-17.123 Ding S, Yang Y, Mei J, Ríos JL. Protective Effects of L‐Malate against Myocardial Ischemia/Reperfusion Injury in Rats. Evidence-Based Complementary and Alternative Medicine 2016; 2016: 3803657.124 He J, Huang L, Sun K, Li J, Han S, Gao X , et al . Oleuropein alleviates myocardial ischemia–reperfusion injury by suppressing oxidative stress and excessive autophagy via TLR4/MAPK signaling pathway. Chinese Medicine 2024; 19: 59.125 Impellizzeri D, Cordaro M, Siracusa R, Fusco R, Peritore AF, Gugliandolo E , et al . Molecular targets for anti-oxidative protection of açaí berry against diabetes myocardial ischemia/reperfusion injury. Free Radical Research 2023; 57: 339-52.126 Li Yg, Li Jh, Wang Hq, Liao J, Du Xy. Cinnamaldehyde protects cardiomyocytes from oxygen‐glucose deprivation/reoxygenation‐induced lipid peroxidation and DNA damage via activating the Nrf2 pathway. Chemical Biology & Drug Design 2024; 103: e14489.127 Lu C, Jiang B, Xu J, Zhang X, Jiang N. Neferine protected cardiomyocytes against hypoxia/oxygenation injury through SIRT1/Nrf2/HO‐1 signaling. Journal of Biochemical and Molecular Toxicology 2023; 37: e23398.128 Wang R, Dong S, Xia R, Sun M, Sun Y, Ren H , et al . Kinsenoside mitigates myocardial ischemia/reperfusion-induced ferroptosis via activation of the Akt/Nrf2/HO-1 pathway. European Journal of Pharmacology 2023; 956: 175985.129 Yan J, Li Z, Liang Y, Yang C, Ou W, Mo H , et al . Fucoxanthin alleviated myocardial ischemia and reperfusion injury through inhibition of ferroptosis via the NRF2 signaling pathway. Food & Function 2023; 14: 10052-68.130 Yan T, Li X, Wang X, Zhang Y, He B, Jia Y , et al . Rhodiola wallichiana var.cholaensis protects against myocardial ischemia-reperfusion injury by attenuating oxidative stress-mediated apoptosis via enhancing Nrf2 signaling. International Journal of Cardiology 2023; 384: 62-73.131 Zhu X, Wu Y, Zhang X, Gu W, Ning Z. Stachydrine ameliorates hypoxia reoxygenation injury of cardiomyocyte via enhancing SIRT1-Nrf2 pathway. Journal of Cardiothoracic Surgery 2023; 18: 265.132 Vatish M, Yamada E, Pessin JE, Bastie CC. Fyn kinase function in lipid utilization: a new upstream regulator of AMPK activity? Arch Physiol Biochem 2009; 115: 191-8.133 Wang SY, Zhu S, Wu J, Zhang M, Xu Y, Xu W , et al . Exercise enhances cardiac function by improving mitochondrial dysfunction and maintaining energy homoeostasis in the development of diabetic cardiomyopathy. J Mol Med (Berl) 2020; 98: 245-61.134 Perrelli M-G. Ischemia/reperfusion injury and cardioprotective mechanisms: Role of mitochondria and reactive oxygen species. World Journal of Cardiology 2011; 3: 186.135 Zaha VG, Qi D, Su KN, Palmeri M, Lee H-Y, Hu X , et al . AMPK is critical for mitochondrial function during reperfusion after myocardial ischemia. Journal of Molecular and Cellular Cardiology 2016; 91: 104-13.136 McGuckin MB, Hutton ARJ, Davis ER, Sabri AHB, Ripolin A, Himawan A , et al . Transdermal Delivery of Pramipexole Using Microneedle Technology for the Potential Treatment of Parkinson’s Disease. Mol Pharm 2024; 21: 2512-33.137 Gong X, Cai J, Zheng W, Huang J, Chen T, Chen W , et al . Isoliquiritigenin alleviates SLC7A11-mediated efferocytosis inhibition to promote wounds healing in diabetes. Biomed Pharmacother 2024; 180: 117578.138 Shen L, Zhu Y, Chen Z, Shen F, Yu W, Zhang L. Isoliquiritigenin attenuates myocardial ischemia reperfusion through autophagy activation mediated by AMPK/mTOR/ULK1 signaling. BMC Cardiovasc Disord 2024; 24: 415.139 Chen Y, Chen H, Chen Y, Yang Z, Zhou T, Xu W. Dexmedetomidine Preconditioning Attenuates Myocardial Ischemia/ Reperfusion Injury in Rats by Suppressing Mitophagy Via Activating Α2-Adrenergic Receptor. Arquivos Brasileiros de Cardiologia 2023; 120: e20220750.140 Yang K, Ma Y, Xie C, He L, Zhao H, Dai Z , et al . Dexmedetomidine combined with propofol attenuates myocardial ischemia/reperfusion injury by activating the AMPK signaling pathway. Heliyon 2023; 9: e22054.141 Liu D, Ding J, Li Z, Lu Y. Pachymic acid (PA) inhibits ferroptosis of cardiomyocytes via activation of the AMPK in mice with ischemia/reperfusion‐induced myocardial injury. Cell Biology International 2023; 48: 46-59.142 Zuo W, Wang L, Tian R, Wang L, Liu Y, Qian H , et al . Dapagliflozin Alleviates Myocardial Ischaemia Reperfusion Injury by Activating Mitophagy via the AMPK-PINK1/Parkin Signalling Pathway. Current Vascular Pharmacology 2024; 22: 203-17.143 Alharbi HO, Sugden PH, Clerk A. Mitogen-activated protein kinase signalling in rat hearts during postnatal development: MAPKs, MAP3Ks, MAP4Ks and DUSPs. Cell Signal 2024; 124: 111397.144 Lv X, Han Y, Li Y, Wang X, Zhang T, Wang X , et al . Nonylphenol displays immunotoxicity by triggering hemocyte extracellular traps in Manila clam via ROS burst, ERK pathway and glycolysis. Ecotoxicol Environ Saf 2024; 285: 117145.145 Kar S, Subbaram S, Carrico PM, Melendez JA. Redox-control of matrix metalloproteinase-1: A critical link between free radicals, matrix remodeling and degenerative disease. Respiratory Physiology & Neurobiology 2010; 174: 299-306.146 Ahn J, Won M, Choi J-H, Kim YS, Jung C-R, Im D-S , et al . Reactive oxygen species-mediated activation of the Akt/ASK1/p38 signaling cascade and p21Cip1 downregulation are required for shikonin-induced apoptosis. Apoptosis 2013; 18: 870-81.147 Shi H, Chen L, Huang J, Lin X, Huang L, Tang M , et al . CSRNP1 Promotes Apoptosis and Mitochondrial Dysfunction via ROS-Mediated JNK/p38 MAPK Pathway Activation in Hepatocellular Carcinoma. Oncology Research 2026; 34: 1-10.148 Lei B, Zhang M, Shi X, Feng N, Yin J, Dong R , et al . Ganoderic acid T, a novel activator of pyruvate carboxylase, exhibits potent anti-liver cancer activity. Metabolism 2025; 170.149 Stensløkken K-O, Rutkovskiy A, Kaljusto M-L, Hafstad AD, Larsen TS, Vaage J. Inadvertent phosphorylation of survival kinases in isolated perfused hearts: a word of caution. Basic Research in Cardiology 2009; 104: 412-23.150 Kitakaze T, Makiyama A, Samukawa Y, Jiang S, Yamashita Y, Ashida H. A physiological concentration of luteolin induces phase II drug-metabolizing enzymes through the ERK1/2 signaling pathway in HepG2 cells. Archives of Biochemistry and Biophysics 2019; 663: 151-9.151 Tian H, Zhang D, Gao Z, Li H, Zhang B, Zhang Q , et al . MDA-7/IL-24 inhibits Nrf2-mediated antioxidant response through activation of p38 pathway and inhibition of ERK pathway involved in cancer cell apoptosis. Cancer Gene Therapy 2014; 21: 416-26.152 Mobasher MA, González-Rodriguez Á, Santamaría B, Ramos S, Martín MÁ, Goya L , et al . Protein tyrosine phosphatase 1B modulates GSK3β/Nrf2 and IGFIR signaling pathways in acetaminophen-induced hepatotoxicity. Cell Death & Disease 2013; 4: e626-e.153 Yan Y, Huang Z, Cheng L, Zhao S, Gao H, Chen K , et al . Dl-3-n-butylphthalide attenuates acute myocardial infarction by inhibiting the binding of Nrf2/Keap1. Toxicology and Applied Pharmacology 2025; 502.154 Das A, Zhu Z, Zhu J, Zhao X, Yang K, Lu L , et al . All-Trans Retinoic Acid Ameliorates Myocardial Ischemia/Reperfusion Injury by Reducing Cardiomyocyte Apoptosis. Plos One 2015; 10: e0133414.155 Jiang W, Zhang Y, Zhang W, Pan X, Liu J, Chen Q , et al . Hirsutine ameliorates myocardial ischemia-reperfusion injury through improving mitochondrial function via CaMKII pathway. Clinical and Experimental Hypertension 2023; 45: 2192444.156 Xu X, Mao C, Zhang C, Zhang M, Gong J, Wang X. Salvianolic Acid B Inhibits Ferroptosis and Apoptosis during Myocardial Ischemia/Reperfusion Injury via Decreasing the Ubiquitin-Proteasome Degradation of GPX4 and the ROS-JNK/MAPK Pathways. Molecules 2023; 28: 4117.157 Qian W, Liu M, Fu Y, Zhang J, Liu W, Li J , et al . Antimicrobial mechanism of luteolin against Staphylococcus aureus and Listeria monocytogenes and its antibiofilm properties. Microbial Pathogenesis 2020; 142: 104056.158 Jiyon Lee, Su-Ho Park, Jintak Lee, Hyunwoo Chun, Myoung-Kwon Choi, Jae-Hwan Yoon , et al . Differential effects of luteolin and its glycosides on invasion and apoptosis in MDA-MB-231 triple-negative breast cancer cells. Excli Journal 2019; 18: 750-63.159 Yu D, Li M, Tian Y, Liu J, Shang J. Luteolin inhibits ROS-activated MAPK pathway in myocardial ischemia/reperfusion injury. Life Sciences 2015; 122: 15-25.160 Adeli O-A, Heidari-Soureshjani S, Rostamian S, Azadegan-Dehkordi Z, Khaghani A. Effects and Mechanisms of Fisetin against Ischemia-reperfusion Injuries: A Systematic Review. Current Pharmaceutical Biotechnology 2024; 25: 2138-53.161 Ye Lin, Xin Yang, Yan Li, De-Jian Huang, Sun Z-Q. A newly synthesized flavone avoids COMT-catalyzed methylation and mitigates myocardial ischemia/reperfusion injury in H9C2 cells via JNK and P38 pathways. Iranian Journal of Basic Medical Sciences 2024; 27: 492-9.162 Lu H, Gong J, Zhang T, Jiang Z, Dong W, Dai J , et al . Leonurine pretreatment protects the heart from myocardial ischemia-reperfusion injury. Experimental Biology and Medicine 2023; 248: 1566-78.163 N D Vaziri, Ding Y. Effect of lead on nitric oxide synthase expression in coronary endothelial cells: role of superoxide. Hypertension 2001; 37: 223-6.164 Lai L-N, Zhang X-J, Zhang X-Y, Song L-H, Guo C-H, Lei J-W , et al . Lazaroid U83836E protects the heart against ischemia reperfusion injury via inhibition of oxidative stress and activation of PKC. Molecular Medicine Reports 2016; 13: 3993-4000.165 Meryem Tuncel, Ram VCS. Hypertensive emergencies Etiology and management. American Journal of Cardiovascular Drugs 2003; 3: 31-.166 E Cornacchia, J Golbus, J Maybaum, J Strahler, S Hanash, Richardson B. Hydralazine and procainamide inhibit T cell DNA methylation and induce autoreactivity. Journal of immunology 1988; 140: 2197-200.167 Tampe B, Tampe D, Zeisberg EM, Müller GA, Bechtel-Walz W, Koziolek M , et al . Induction of Tet3-dependent Epigenetic Remodeling by Low-dose Hydralazine Attenuates Progression of Chronic Kidney Disease. EBioMedicine 2015; 2: 19-36.168 Li C, Su Z, Ge L, Chen Y, Chen X, Li Y. Cardioprotection of hydralazine against myocardial ischemia/reperfusion injury in rats. European Journal of Pharmacology 2020; 869: 172850.169 Alamdari AF, Rahnemayan S, Rajabi H, Vahed N, Kashani HRK, Rezabakhsh A , et al . Melatonin as a promising modulator of aging related neurodegenerative disorders: Role of microRNAs. Pharmacological Research 2021; 173.170 Joseph TT, Schuch V, Hossack DJ, Chakraborty R, Johnson EL. Melatonin: the placental antioxidant and anti-inflammatory. Frontiers in Immunology 2024; 15.171 Bonetti M, Giugno L, Borsani E, Bonomini F. Potential Neuroprotective Effect of Melatonin in the Hippocampus of Male BTBR Mice. Nutrients 2024; 16.172 Weiwei Zhi, Kai Li, Hongbing Wang, Ming Lei, Guo Y. Melatonin elicits protective effects on OGD/R‑insulted H9c2 cells by activating PGC‑1α/Nrf2 signaling. International Journal of Molecular Medicine 2020; 45: 1294-304.173 Pagliaro P, Penna C. Inhibitors of NLRP3 Inflammasome in Ischemic Heart Disease: Focus on Functional and Redox Aspects. Antioxidants 2023; 12: 1396.174 Wang S, Chen Y, Wu C, Wang Y, Lin W, Bu R. Trehalose Alleviates Myocardial Ischemia/Reperfusion Injury by Inhibiting NLRP3-Mediated Pyroptosis. Applied Biochemistry and Biotechnology 2023; 196: 1194-210.175 Shurong L, Xiang L, Fang X, Yang B, Jun M. Melatonin reduces myocardial cell damage in myocardial ischemia/reperfusion rats by inhibiting NLRP3 activation. Cellular and Molecular Biology 2023; 69: 259-64.176 Guo J, Wang S, Wan X, Liu X, Wang Z, Liang C , et al . Mitochondria-derived methylmalonic acid aggravates ischemia–reperfusion injury by activating reactive oxygen species-dependent ferroptosis. Cell Communication and Signaling 2024; 22: 53.177 Fang M, Li T, Wu Z. Wtap-Mediated M6a Modification of Klf6 Aggravates Hypoxia/Reoxygenation-Induced Human Cardiomyocyte Injury. Shock 2024; 62: 201-7.178 Jiang W, Yan Z, Zheng X, Huang S, Hu Y, Xiong F , et al . Targeting the Ferroptosis and Endoplasmic Reticulum Stress Signaling Pathways by CBX7 in Myocardial Ischemia/reperfusion Injury. Cell Biochemistry and Biophysics 2024; 82: 2171-81.179 Hu T, Hu F-J, Huang H, Zhang Z-Y, Qiao Y-M, Huang W-X , et al . Epigallocatechin-3-gallate confers protection against myocardial ischemia/reperfusion injury by inhibiting ferroptosis, apoptosis, and autophagy via modulation of 14–3-3η. Biomedicine & Pharmacotherapy 2024; 174: 116542.180 Hu T, Yu W-p, Wang X-q, Wang Z-y, Xu Z-q, Hu F-j , et al . Activation of PPAR-α attenuates myocardial ischemia/reperfusion injury by inhibiting ferroptosis and mitochondrial injury via upregulating 14-3-3η. Scientific Reports 2024; 14: 15246.181 Kong Junhong, Tsai Yun, Shui Guangxing, Ding Yuhan, Xiang Qian, Haowen Z. (-)-Epicatechin protects against myocardial ischemia/reperfusion injury via autophagy-dependent ferroptosis. Aging (Albany NY) 2024; 16: 2181-93.182 Wu Z, Bai Y, Qi Y, Chang C, Jiao Y, Bai Y , et al . Metformin ameliorates ferroptosis in cardiac ischemia and reperfusion by reducing NOX4 expression via promoting AMPKα. Pharmaceutical Biology 2023; 61: 886-96.183 Zhao L, Shi H, Zhang F, Xue H, Han Q. Hederagenin protects against myocardial ischemia–reperfusion injury via attenuating ALOX5-mediated ferroptosis. Naunyn-Schmiedeberg’s Archives of Pharmacology 2023; 397: 3411-24.184 Xiang K, Wu H, Liu Y, Wang S, Li X, Yang B , et al . MOF-derived bimetallic nanozyme to catalyze ROS scavenging for protection of myocardial injury. Theranostics 2023; 13: 2721-33.185 Luo J, Molbay M, Chen Y, Horvath I, Kadletz K, Kick B , et al . Nanocarrier imaging at single-cell resolution across entire mouse bodies with deep learning. Nature Biotechnology 2025; 43: 2009-22.186 Yao W, Lin Y, Weng Y, Wu Y, Zheng L, Zheng D , et al . Lipid‐Based Nanoparticles in Cancer Therapy: Advances in Targeted Drug Delivery and Therapeutic Potential for Renal Cell Carcinoma. Advanced Science 2025; 12.187 Yu W, Ding J, Chen J, Jiang Y, Zhao J, Liu J , et al . Magnesium Ion-Doped Mesoporous Bioactive Glasses Loaded with Gallic Acid Against Myocardial Ischemia/Reperfusion Injury by Affecting the Biological Functions of Multiple Cells. International Journal of Nanomedicine 2024; 19: 347-66.188 Chen C, Liu W, Gu X, Zhang L, Mao X, Chen Z , et al . Baicalin-loaded Polydopamine modified ZIF-8 NPs inhibits myocardial ischemia/reperfusion injury in rats. Journal of Biomaterials Science, Polymer Edition 2024; 35: 1863-78.189 Huang Y, Lu J, Zhao L, Fu X, Peng S, Zhang W , et al . Retinal cell-targeted liposomal ginsenoside Rg3 attenuates retinal ischemia-reperfusion injury via alleviating oxidative stress and promoting microglia/macrophage M2 polarization. Free Radical Biology and Medicine 2023; 206: 162-79.190 Li L, Wang Y, Guo R, Li S, Ni J, Gao S , et al . Ginsenoside Rg3-loaded, reactive oxygen species-responsive polymeric nanoparticles for alleviating myocardial ischemia-reperfusion injury. Journal of Controlled Release 2020; 317: 259-72.191 Li N, Huang C, Zhang J, Zhang J, Huang J, Li S , et al . Chemotactic NO/H2S Nanomotors Realizing Cardiac Targeting of G-CSF against Myocardial Ischemia-Reperfusion Injury. ACS Nano 2023; 17: 12573-93.192 Wang Z, Yang N, Hou Y, Li Y, Yin C, Yang E , et al . L‐Arginine‐Loaded Gold Nanocages Ameliorate Myocardial Ischemia/Reperfusion Injury by Promoting Nitric Oxide Production and Maintaining Mitochondrial Function. Advanced Science 2023; 10: e2302123.193 Ye T, Chen C, Wang D, Huang C, Yan Z, Chen Y , et al . Protective effects of Pt-N-C single-atom nanozymes against myocardial ischemia-reperfusion injury. Nature Communications 2024; 15: 1682.194 Zhu Y, Matsumura Y, Velayutham M, Foley LM, Hitchens TK, Wagner WR. Reactive oxygen species scavenging with a biodegradable, thermally responsive hydrogel compatible with soft tissue injection. Biomaterials 2018; 177: 98-112. Supplementary Material File (figures.pptx) Download 5.66 MB Information & Authors Information Version history V1 Version 1 14 February 2026 Copyright This work is licensed under a Non Exclusive No Reuse License. Authors Affiliations Jingsong Wang Guangyuan Central Hospital View all articles by this author Heping Li Guangyuan Central Hospital View all articles by this author Qiong Shao Ezhou Central Hospital View all articles by this author Yang Zhao Guangyuan Central Hospital View all articles by this author Xueqin Yang Guangyuan Central Hospital View all articles by this author Mei Fan Guangyuan Central Hospital View all articles by this author Heng Gan Luzhou Hospital of Traditional Chinese Medicine Southwest Medical University View all articles by this author Qian Tang Guangyuan Central Hospital View all articles by this author Shuang Jiang Chongqing Normal University View all articles by this author Jingwen Xie [email protected] Chongqing Normal University View all articles by this author Metrics & Citations Metrics Article Usage 178 views 62 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Jingsong Wang, Heping Li, Qiong Shao, et al. 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