Magnesium sulfate in oxidative stress-associated pathologies: clinical, cellular, and molecular perspectives.

Magnesium sulfate (MgSO₄) is a therapeutically versatile agent used across various medical conditions. This review integrates experimental and computational findings to elucidate the clinical, cellular, molecular, and electronic mechanisms underlying MgSO₄’s therapeutic effects, focusing on its antioxidant properties. MgSO₄ remains the gold standard treatment for preeclampsia and eclampsia, preventing seizures and mitigating oxidative damage. In preterm birth, it offers fetal neuroprotection, although its efficacy as a tocolytic agent is limited. MgSO₄ also shows promise in treating respiratory conditions, notably severe asthma, where it acts as a bronchodilator. Its applications extend to anesthesia, pain management, and cardiac arrhythmias, reflecting its diverse pharmacological actions. Advanced computational methods, including molecular dynamics simulations and quantum chemistry calculations, have revealed how MgSO₄ interacts with cell membranes and neutralizes hydroxyl radicals. These studies suggest that MgSO₄’s antioxidant effects stem from its ability to stabilize membrane structures and modulate electron transfer processes. The therapeutic effects are mediated through multiple pathways, including calcium channel modulation, NMDA receptor antagonism, and anti-inflammatory mechanisms. Although generally safe, MgSO₄ requires careful monitoring due to its narrow therapeutic window. Future research should focus on precision dosing strategies, innovative delivery systems, and expanded therapeutic applications. A comprehensive understanding of MgSO₄’s molecular mechanisms and clinical applications will further optimize its therapeutic use. Graphical abstract

Magnesium sulfate, Oxidative stress, Molecular tools, Molecular dynamics simulations, Quantum chemistry calculations

Translational medicine bridges preclinical research and clinical practice, integrating diverse scientific disciplines to advance healthcare solutions and improve patient outcomes. This interdisciplinary field synthesizes knowledge from physics, chemistry, biology, biochemistry, immunology, and clinical medicine to revolutionize our approach to understanding disease mechanisms, developing targeted treatments, and implementing personalized medicine strategies (Boccellino 2023). Magnesium sulfate (MgSO₄) exemplifies a crucial medication that has maintained its significance in contemporary medicine since its discovery centuries ago. Today, it plays vital roles in various medical fields, including as an anticonvulsant in preeclampsia and eclampsia, a tocolytic agent in preterm labor, a bronchodilator in severe asthma, and a vital supplement in cases of hypomagnesemia (Abad et al. 2005a; Chiarello et al. 2018). Despite its widespread use and proven clinical effectiveness, the precise molecular mechanisms underlying MgSO₄’s therapeutic effects remain incompletely understood. The drug exhibits multiple pharmacological actions, acting as a calcium antagonist, modulating neurotransmitter release, demonstrating anti-inflammatory properties, and showing antioxidant effects (Marín et al. 2023). These diverse mechanisms contribute to its therapeutic versatility but also highlight the complexity of its action (Del Castillo and Engbaek 1954; Pritchard 1980; Sibai et al. 1984). Modern scientific approaches, including advanced molecular techniques, high-throughput screening, proteomics, metabolomics, and computational chemistry, are now being used to unravel the intricate mechanisms of MgSO₄’s therapeutic effects. Understanding these mechanisms is crucial not only for optimizing current treatments but also for identifying novel therapeutic applications and potential drug combinations that could enhance their efficacy (Fawcett et al. 1999; Fernández et al. 2017, 2021, 2024; Houston 2011; Kirkland et al. 2018; Romani 2011; Sugimoto et al. 2012). This comprehensive review investigates the therapeutic applications of MgSO₄, examining its significant contributions to obstetrics, neurology, pulmonology, and critical care medicine. By integrating clinical observations with modern scientific methodologies, we provide an in-depth analysis of this versatile compound’s molecular mechanisms, pharmacokinetic properties, and therapeutic potential. This systematic knowledge synthesis enhances our understanding of MgSO₄’s current clinical applications, potentially leading to optimized dosing strategies, innovative drug delivery systems, and expanded therapeutic applications. Is MgSO4 a potential panacea? a critical analysis in modern medicine MgSO₄ exhibits a diverse pharmacological profile with clinical applications spanning multiple medical specialties. It is utilized in obstetrics for preeclampsia with severe features, in pulmonology for severe asthma exacerbations, in cardiology for specific arrhythmias, and in critical care for neuroprotection in conditions such as preterm birth and hypoxic-ischemic events (Euser and Cipolla 2009; Ho 2008; Marret et al. 2007; Rowe et al. 2000). Despite its versatility, MgSO₄ presents therapeutic limitations and practical challenges. A narrow therapeutic window necessitates precise dosing and careful monitoring to ensure efficacy while minimizing potential toxicity. Table 1 summarizes the beneficial and adverse effects of MgSO₄ therapy in clinical practice. Regular assessment of serum magnesium levels is crucial, particularly in critically ill patients or those with impaired renal functions. Furthermore, the drug’s effectiveness varies significantly among individuals, influenced by genetic polymorphisms affecting magnesium transport, concurrent medications, and underlying pathophysiology. Implementation challenges include considerations regarding administration routes, monitoring requirements, resource constraints in diverse healthcare settings, patient characteristics, and risk–benefit profiles (Curry and Yu 2018; Lu and Nightingale 2000; Shepherd et al. 2024; Sibai 2005). Table 1. | Beneficial effects | Adverse Effects | |---|---| | Obstetric/neonatal: (Bain et al. 2013; Crowther et al. 2003; Euser and Cipolla 2009; Ghia et al. 2000; Wolf et al. 2020) | | | • Potential reduction in cerebral palsy in preterm infants • Significant reduction in substantial gross motor dysfunction • Reduction in moderate to severe cerebral palsy in infants born before 32 weeks gestation | • Can prolong labor and increase cesarean delivery rates • Impaired attention and working memory in patients undergoing preterm labor treatment • May increase postpartum bleeding | | Cardiovascular: (James et al. 2018; Liu et al. 2024; Liu and Dudley 2020; Nakaigawa et al. 1997) | | | • Potential treatment for polymorphic ventricular tachycardia (torsades de pointes) associated with long QT interval • May prevent arrhythmias in acute coronary syndrome if hypomagnesemia is present • Shortens QT interval, reducing susceptibility to ventricular tachycardia • Slows conduction through AV node, reducing heart rate in polymorphic VT with long QT interval • Lowers mean arterial pressure and systolic vascular resistance in heart failure patients • Reduces frequency of ventricular arrhythmias in heart failure patients | • Vasodilation resulting in flushing and hypotension • May encourage hypotension and cardiac arrhythmias in cases of hypermagnesemia | | Pulmonary: (Knightly et al. 2017; Lindeman et al. 1989; Mowafi et al. 2023; Ni et al. 2022; Vyata et al. 2022) | | | • Bronchodilation: effective as a bronchodilator • Reduction in airway reactivity: significant decrease in bronchial hyperreactivity • Improvement in lung function: slight increase in lung volumes (9%) • Attenuation of hypocapnia-induced bronchoconstriction • Maintenance of dynamic lung compliance during general anesthesia • Prevention of increase in dead space during mechanical ventilation • Potential reduction in hospital admissions for acute asthma exacerbations when used with bronchodilators • Relief of wheezing and airway narrowing in asthma patients | • May decrease breathing rate • Risk of respiratory depression • Rare cases of pulmonary edema | | Neurological: (Chollat and Marret 2018; Temkin et al. 2007; Zheng et al. 2023) | | | • Possible neuroprotective effects through NMDA receptor antagonism • Potential neuroprotective effects in cardiac arrest models • Reduces cerebral injury and preserves neurologic function in animal models of global ischemia | • Can decrease neuromuscular transmission • Potential negative effects in traumatic brain injury treatment, including worse outcomes at lower doses and higher mortality at higher doses • Slight increase in pulmonary edema and respiratory failure risk at lower magnesium target levels in traumatic brain injury patients | | General: (Arumugam et al. 2021; Dahake et al. 2024; De Zoysa et al. 2022; Eisenbud and LoBue 1976; Gutiérrez-Román et al. 2022; Hunter and Gibbins 2011) | | | • Causes smooth muscle relaxation by reducing intracellular calcium-binding • Manages hypomagnesemia and tetany • Treats acute nephritis in children | • Common side effects: flushing, increased warmth, sweating, nausea, vomiting, headaches, muscle weakness, blurred vision • Rare but severe consequences of iatrogenic overdose, including respiratory arrest, cardiac arrest, and death | Contemporary research continually reveals new potential applications while clarifying the boundaries of MgSO₄’s therapeutic utility. Advanced molecular techniques and rigorous clinical trials are enhancing our understanding of its mechanisms of action, uncovering previously unknown cellular and systemic effects. This ongoing elucidation of molecular mechanisms, alongside refinements in administration protocols and monitoring strategies, continues to solidify its role in modern medicine. Despite not being a panacea, MgSO₄ retains its value as a therapeutic agent, especially in critical care, obstetrics, and acute care contexts, owing to its multifaceted mechanisms of action capable of addressing intricate pathophysiological conditions. MgSO₄ and preeclampsia with severe features Preeclampsia is a complex, pregnancy-specific syndrome characterized by multisystem involvement (Lambert et al. 2014). The International Society for the Study of Hypertension in Pregnancy (ISSHP) defines it as new-onset hypertension accompanied by one or more additional features, including proteinuria, organ dysfunction, or fetal growth restriction (Brown et al. 2018). While the exact etiology remains unclear, preeclampsia is believed to arise from placental abnormalities (early-onset) or maternal metabolic disturbances (late-onset) (Phipps et al. 2019). Eclampsia, a critical complication of preeclampsia, involves the onset of generalized tonic–clonic seizures (Magley and Hinson 2024). MgSO₄ is a crucial treatment for preeclampsia and eclampsia, exhibiting multifaceted mechanisms of action across various physiological systems (Table 2). In the central nervous system, it blocks NMDA receptors, reducing neuronal excitability and seizures (Cotton et al. 1992), while also protecting the blood–brain barrier (Euser and Cipolla 2009). At the neuromuscular junction, MgSO₄ reduces calcium influx and acetylcholine release, relaxing muscle tone (Altura et al. 1987). Vascularly, it promotes vasodilation, enhances blood flow, and reduces systemic vascular resistance (Chiarello et al. 2018; Xing et al. 2024). MgSO₄ also provides endothelial protection through anti-inflammatory and antioxidant properties (Chiarello et al. 2018) and suppresses the NF-κB pathway in the placenta (Wu et al. 2023). At the cellular level, it reduces lipid peroxidation, restores Ca-ATPase activity (Abad et al. 2005b), and protects syncytiotrophoblast plasma membranes (Chiarello et al. 2014). These diverse actions collectively contribute to MgSO₄’s effectiveness in managing preeclampsia and eclampsia. Table 2. | Main target of MgSO4 | Described effects of MgSO4 in preeclamptic women | Reference | |---|---|---| | Central nervous system effects | • MgSO₄ blocks N-methyl-D-aspartate (NMDA) receptors in the brain, reducing neuronal excitability and suppressing seizures • It protects the blood–brain barrier, reducing cerebral edema and enhancing its anticonvulsant effects | (Cotton et al. 1992) (Euser and Cipolla 2009) | | Neuromuscular junction | • MgSO₄ decreases calcium influx and acetylcholine release, reducing muscle contractility and relaxing muscle tone | (Altura et al. 1987) | | Vascular effects | • Promotes vasodilation by stimulating prostacyclin and nitric oxide (NO) synthesis, alleviating cerebral ischemia • Enhances cerebral, uterine, and renal blood flow while reducing systemic vascular resistance • Lowers renin and angiotensin-converting enzyme activity • Diminishes platelet aggregation | (Chiarello et al. 2018) (Xing et al. 2024) (Sipes et al. 1989) (Sheu et al. 2002) | | Endothelial protection | • MgSO₄’s anti-inflammatory and antioxidant properties protect endothelial cells from oxidative stress • Reduces peroxide-induced vasoconstriction in the placenta by inhibiting thromboxane synthesis • Suppresses the NF-κB pathway, reducing placental inflammation and improving function | (Chiarello et al. 2018) (Walsh et al. 1998) (Wu et al. 2023) | | Cellular protection | • Reduces lipid peroxidation and osmotic fragility in red blood cells • Restores calcium-stimulated ATPase (Ca-ATPase) activity in red blood cells • Protects syncytiotrophoblast membranes by lowering TBARS levels during hypoxia • Acts as an antioxidant, quenching reactive oxygen species (ROS) and partially inhibiting lipid peroxidation | (Abad et al. 2010) (Abad et al. 2005b) (Chiarello et al. 2014) (Abad et al. 2015b) | These multifaceted mechanisms contribute to MgSO₄’s efficacy in preventing and treating eclampsia, as well as potentially reducing the risk of cerebral palsy in preterm infants (Nelson and Grether 1995). However, it is important to note that MgSO₄ can also cause side effects, including reduced uterine activity, prolonged labor, increased postpartum blood loss, and lowered fetal heart rate (Sibai 1990). The effectiveness of MgSO₄ in eclampsia management has been demonstrated through numerous clinical studies, including the MAGPIE trial, which reported a 50% reduction in eclampsia risk among preeclamptic patients (Altman et al. 2002). This evidence has led to its endorsement by the World Health Organization as the preferred treatment for convulsion prevention in at-risk pregnancies (Goldenberg et al. 2015). Effect of MgSO4 in salt-loaded pregnant rats Our understanding of preeclampsia’s pathophysiological mechanisms has advanced through combined insights from animal studies and human clinical research (Bakrania et al. 2022). Various animal models have been developed to study the condition’s diverse pathways, with our research focusing on salt-loaded pregnant rats as an experimental model. These salt-loaded pregnant rats exhibit numerous characteristics parallel to human preeclampsia, including elevated systolic blood pressure, proteinuria, enhanced oxidative and nitrosative stress, and reduced fetal growth (Beauséjour et al. 2003; Rojas et al. 2025, 2016). They also demonstrate decreased renin–angiotensin–aldosterone system activity (Beauséjour et al. 2003), an elevated thromboxane/prostacyclin ratio (Beauséjour et al. 2007a), and reduced uterine artery and placental measurements (Beauséjour et al. 2007b). Furthermore, like preeclamptic women, salt-loaded pregnant rats show altered vascular responsiveness compared to normal pregnancies (St-Louis et al. 2006). The similarities between salt-loaded rats and preeclamptic women extend beyond clinical manifestations. Both exhibit increased oxidative stress markers, compromised antioxidant defenses, and altered membrane transport systems (Beauséjour et al. 2003, 2007a, b; Rojas et al. 2016). Notably, both demonstrate disrupted calcium homeostasis, reflected in reduced Ca-ATPase activity in placental tissue and red blood cells (Abad et al. 2012, 2015a; Matteo et al. 1998; Rojas et al. 2025). Furthermore, parallel changes in red blood cell osmotic fragility and lipid peroxidation levels underscore the model’s relevance (Abad et al. 2012, 2015a; Gutiérrez et al. 2009; Rojas et al. 2025). Contextualizing these findings within the broader scientific literature, increased lipid peroxidation in preeclampsia has been widely reported. Recent research has established a link between premature placental senescence, oxidative stress, and lipid oxidation-derived aldehydes, as well as their connections to preeclampsia (Negre-Salvayre et al. 2022). The reduction in Ca-ATPase activity observed in our model aligns with findings from other research groups (Dai and Chou 1994; Hung 2007). Increased peripheral vascular resistance is a cardinal feature of preeclampsia. In this context, Wimalasundera et al. (2010) analyzed the relaxation and decline of intracellular Ca2+ during recovery from activation of isolated resistance arteries, finding it impaired during preeclampsia. They proposed that this impairment may be mediated by decreased plasma membrane Ca-ATPase activity, potentially contributing to elevated peripheral resistance and raised blood pressure in preeclampsia. This hypothesis aligns with our findings regarding Ca-ATPase activity in both preeclamptic pregnant women and salt-loaded pregnant rats. Abad et al. (2015b) demonstrated that MgSO₄ treatment reduced lipid peroxidation and increased Ca-ATPase activity in placental tissue and red blood cell ghosts from preeclamptic women. Our laboratory has corroborated these effects of MgSO₄ in the salt-loaded rat model (Rojas et al. 2025). These collective findings have opened new avenues to investigate the potential role of MgSO₄ as an antioxidant in preeclampsia (see sections “Oxidative stress and MgSO4” and “Unveiling the role of MgSO4 as an antioxidant with computational chemistry” for further discussion). MgSO₄, preterm birth, and fetal neuroprotection Our understanding of preeclampsia’s pathophysiological mechanisms has significantly advanced through insights gained from both animal studies and human clinical research (Bakrania et al. 2022). Animal models are invaluable tools for dissecting the complex pathways involved in this condition, and our research utilizes salt-loaded pregnant rats as a relevant experimental model. These salt-loaded pregnant rats exhibit several characteristics that closely mirror human preeclampsia, including elevated systolic blood pressure, proteinuria, increased oxidative and nitrosative stress, and reduced fetal growth (Beauséjour et al. 2003; Rojas et al. 2025, 2016). Furthermore, they demonstrate decreased activity of the renin–angiotensin–aldosterone system (Beauséjour et al. 2003), an elevated thromboxane/prostacyclin ratio (Beauséjour et al. 2007a), and reduced uterine artery and placental measurements (Beauséjour et al. 2007b). Consistent with observations in preeclamptic women, salt-loaded pregnant rats also display altered vascular responsiveness compared to normal pregnancies (St-Louis et al. 2006). The similarities between salt-loaded rats and preeclamptic women extend beyond clinical manifestations. Both exhibit increased markers of oxidative stress, compromised antioxidant defenses, and altered membrane transport systems (Beauséjour et al. 2003, 2007a, b; Rojas et al. 2016). Notably, both demonstrate disrupted calcium homeostasis, reflected in reduced Ca-ATPase activity in placental tissue and red blood cells (Abad et al. 2012, 2015a; Matteo et al. 1998; Rojas et al. 2025). Parallel changes in red blood cell osmotic fragility and lipid peroxidation levels further underscore the model’s relevance (Abad et al. 2012, 2015a; Gutiérrez et al. 2009; Rojas et al. 2025). Contextualizing these findings within the broader scientific literature, increased lipid peroxidation in preeclampsia has been widely reported. Recent research has established a link between premature placental senescence, oxidative stress, and lipid oxidation-derived aldehydes, highlighting their connections to preeclampsia (Negre-Salvayre et al. 2022). The reduction in Ca-ATPase activity observed in our model aligns with findings from other research groups (Dai and Chou 1994; Hung 2007). Increased peripheral vascular resistance is a cardinal feature of preeclampsia. In this context, Wimalasundera et al. (2010) analyzed the relaxation and decline of intracellular Ca2 + during recovery from activation of isolated resistance arteries, finding it impaired during preeclampsia. They proposed that this impairment may be mediated by decreased plasma membrane Ca-ATPase activity, potentially contributing to elevated peripheral resistance and raised blood pressure in preeclampsia. This hypothesis aligns with our findings regarding Ca-ATPase activity in both preeclamptic pregnant women and salt-loaded pregnant rats. Abad et al. (2015b) demonstrated that MgSO₄ treatment reduced lipid peroxidation and increased Ca-ATPase activity in placental tissue and red blood cell ghosts from preeclamptic women. Our laboratory has corroborated these effects of MgSO₄ in the salt-loaded rat model (Rojas et al. 2025). These collective findings have opened new avenues to investigate the potential role of MgSO₄ as an antioxidant in preeclampsia (see sections “Oxidative stress and MgSO4” and “Unveiling the role of MgSO4 as an antioxidant with computational chemistry” for further discussion). MgSO₄ and the cardiometabolic risk during pregnancy Pregnancy induces significant physiological changes that impact a woman’s cardiovascular, immune, and metabolic systems, potentially revealing predispositions to cardiometabolic disorders (CMDs). Women with a history of hypertensive disorders of pregnancy (including preeclampsia), gestational diabetes mellitus, spontaneous preterm birth, or delivering small-for-gestational-age babies face an elevated risk of developing CMDs later in life, such as cardiovascular disease, stroke, type 2 diabetes, and chronic kidney disease (Nagraj et al. 2020). Magnesium plays a crucial role in maintaining cardiovascular function during pregnancy, with multifaceted effects on both microvascular and macrovascular systems (Fritzen et al. 2023; Mubagwa et al. 2007). In the microvasculature, magnesium acts as a vasodilator, improving blood flow in small vessels and capillaries. This effect is particularly important in organs like the placenta, where it enhances nutrient and oxygen exchange (Yogi et al. 2010). In the macrovasculature, magnesium modulates vascular smooth muscle tone, helping to control blood pressure in larger arteries (Longo et al. 2001). At the cellular level, magnesium acts as a natural calcium channel blocker, primarily by inhibiting L-type calcium channels in cardiomyocytes and vascular smooth muscle cells. This action prevents excessive calcium influx, preserving normal heart muscle contractility and vascular tone (Mubagwa et al. 2007). In the myocardium, magnesium also modulates Na,K-ATPase activity and influences sarcoplasmic reticulum calcium ATPase (SERCA) function, collectively maintaining cardiac rhythm and contractility (Vishnu et al. 2024). The vascular effects of magnesium occur through multiple mechanisms: stimulating nitric oxide production (important for both micro- and macrovascular function), reducing intracellular Ca2 + in vascular smooth muscle cells, and modulating endothelin-1 action (Tang et al. 2018). Low magnesium levels are associated with both microvascular dysfunction (e.g., in the placenta) and macrovascular issues (e.g., hypertension), potentially contributing to preeclampsia development (Makrides et al. 2014; Zarean and Tarjan 2017). Intravenous MgSO₄ treatment in preeclamptic women affects both micro- and macrovascular systems. It stabilizes electrolyte concentrations, reduces arrhythmias by decreasing the QT interval and increasing the refractory period, and lowers both systolic and diastolic blood pressures (Duley et al. 2010; Zarean and Tarjan 2017). In the microvasculature, MgSO₄ improves endothelial function and reduces oxidative stress, while in larger vessels, it offers cardioprotective effects during ischemia–reperfusion events by limiting infarct size, reducing coronary artery spasm, and decreasing reperfusion injury (Vishnu et al. 2024). In glucose metabolism, magnesium enhances insulin sensitivity by promoting glucose transporter 4 (GLUT4) translocation to the cell membrane and activating tyrosine kinase on insulin receptors (Mubagwa et al. 2007). This action affects both micro- and macrovascular function by improving glucose uptake in tissues and maintaining normal blood glucose levels, which is crucial for vascular health (Luo et al. 2024; Naowar et al. 2024). Magnesium deficiency is associated with an elevated risk of gestational diabetes mellitus (GDM), which can lead to both micro- and macrovascular complications (Musavi et al. 2019). Studies have shown that magnesium supplementation may reduce biomarkers of inflammation and oxidative stress, benefiting both small and large blood vessels (Jamilian et al. 2019). These mechanisms highlight magnesium’s importance in maintaining cardiovascular health during pregnancy, affecting both micro- and macrovascular systems. The multifaceted actions of magnesium underscore its significance in obstetric care, particularly in managing hypertensive disorders of pregnancy and their associated vascular complications (Makrides et al. 2014; Vishnu et al. 2024; Zarean and Tarjan 2017). MgSO₄ and pre-pregnancy obesity The use and suitability of MgSO₄ in patients with critical conditions like pre-pregnancy obesity or high BMI is an increasingly relevant concern in obstetric care. Recent studies have shed light on the pharmacokinetics and efficacy of MgSO₄ in these populations. Obese women with preeclampsia tend to have lower serum magnesium levels during intravenous MgSO₄ infusion, potentially reducing the likelihood of achieving therapeutic levels (Ramadan et al. 2022). A negative correlation between body mass index (BMI) and serum magnesium levels at 4 and 8 h after infusion has been observed (Ramadan et al. 2022). Overweight and obese women may require higher maintenance doses of MgSO₄ to reach therapeutic levels due to differences in pharmacokinetics and drug distribution (Kitiyodom 2016; Pascoal et al. 2019). However, the optimal dosing strategy for these patients is still under investigation. Despite concerns about dosing, a study of women who received MgSO₄ for fetal neuroprotection found that maternal obesity was not associated with an increased risk of cerebral palsy or death in children after adjusting for gestational age at delivery (McPherson et al. 2015). Research has shown that a significant proportion of obese women do not achieve therapeutic MgSO₄ levels after either a 4-g or 6-g loading dose (De Zoysa et al. 2022). This suggests that current standard dosing protocols may be inadequate for obese patients. Given the potential for subtherapeutic levels or toxicity, close monitoring of MgSO₄ therapy is crucial, especially in obese patients (Kitiyodom 2016; Pascoal et al. 2019). Frequent assessment of signs of hypermagnesemia, such as loss of patellar reflexes, is recommended. These findings highlight the need for tailored treatment regimens that consider patient weight and renal function to maximize efficacy and minimize toxicity in obese and overweight pregnant women (Brookfield and Mbata 2023). Further research is needed to establish optimal dosing protocols for this growing patient population. MgSO4 and asthma Asthma is a common and heterogeneous chronic respiratory condition characterized by airway inflammation, bronchoconstriction, and increased mucus production, leading to symptoms such as wheezing, shortness of breath, chest tightness, and coughing (Gibson and McDonald 2024). These symptoms result from the hyperresponsiveness of the airways to various triggers, including allergens, infections, and environmental factors (Hsieh et al. 2023). In acute asthma episodes or severe exacerbations, airway obstruction can intensify, leading to severe breathing difficulties that may require medical intervention and can be unpredictable and life-threatening (Demoule et al. 2020). MgSO₄ has been proposed as an additional treatment for severe, life-threatening asthma attacks. Potentially, MgSO₄ may relax bronchial smooth muscles in a dose-dependent manner by limiting calcium entry into cells (Fatima et al. 2024), reducing histamine release from mast cells, and decreasing acetylcholine release from cholinergic nerves (Song and Chang 2012). Additionally, MgSO₄ may enhance the bronchodilator effects of β2-agonists by increasing their receptor affinity. IV MgSO₄ has proven effective in reducing hospital admissions and enhancing lung function in adults with severe asthma exacerbations that do not respond to standard treatments like inhaled beta-agonists and corticosteroids (Green 2016). However, the evidence for nebulized MgSO₄ as an additional therapy remains inconclusive, with limited data supporting its impact on hospital admissions or overall asthma control (Song and Chang 2012). Despite its demonstrated benefits in improving lung function (Rovsing et al. 2023), variations in dosing protocols, patient selection, and administration methods across studies contribute to inconsistent findings and highlight the need for standardized guidelines (Ni et al. 2022). Furthermore, a gap persists between evidence-based recommendations and clinical practice, as MgSO₄ remains underutilized in some emergency departments for treating severe asthma. Current guidelines from organizations like the Global Initiative for Asthma (GINA) endorse MgSO₄ for severe asthma cases unresponsive to conventional therapies, though it is not recommended for routine asthma management (Rajvanshi et al. 2024). MgSO₄ is generally safe, with only minor side effects such as flushing and mild fatigue, which are typically transient. In pediatric cases, MgSO₄ has also emerged as a valuable adjunct therapy for severe asthma exacerbations, particularly in children who do not respond to standard treatments. Evidence indicates that IV MgSO₄, administered as a single dose (50–75 mg/kg) or as a high-dose continuous infusion (200 mg/kg/4 h), can effectively reduce hospital admissions and improve respiratory function in emergency settings (Irazuzta and Chiriboga 2017). By promoting bronchial smooth muscle relaxation and minimizing airway inflammation, early MgSO₄ administration has proven to be a cost-effective approach in managing acute asthma in children, with minimal side effects and a strong safety profile. MgSO₄ and chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is a progressive lung condition characterized by airway inflammation and obstruction, which restricts airflow in and out of the lungs (Vogelmeier et al. 2017). Common symptoms include difficulty breathing, a chronic mucus-producing cough, and wheezing. COPD is primarily caused by prolonged exposure to irritants like cigarette smoke, dust, fumes, or chemicals (Agarwal et al. 2025). The condition typically encompasses emphysema and chronic bronchitis, which often coexist and vary in severity among individuals. A recent Cochrane review evaluated the effectiveness of MgSO₄ in managing acute exacerbations of COPD, analyzing data from seven randomized controlled trials (RCTs) comparing IV MgSO₄ to placebo (Ni et al. 2022). The findings suggest that MgSO₄ may reduce hospital admissions, shorten hospital stays, and improve dyspnea scores in patients with COPD exacerbations. However, its effects on other clinical outcomes, including lung function, oxygen saturation, and the need for non-invasive ventilation, remain inconclusive due to limited available data (Ni et al. 2022). Two RCTs published in 2021 assessed the impact of MgSO₄ on airflow obstruction using different parameters. Jahanian et al. found no significant improvement in forced expiratory volume in one second (FEV1) with a 2 g dose of MgSO₄ (Jahanian et al. 2021), while Vafadar et al. reported a notable increase in peak expiratory flow rate (PEFR) with a 2.5 g dose (Vafadar Moradi et al. 2021). These studies presented conflicting findings on dyspnea scores and showed no significant effect on oxygen saturation. Smaller studies have shown contradictory results regarding MgSO₄’s effect on airflow. One study demonstrated significant improvements in both FEV1 and forced vital capacity (FVC) with a 2 g dose (Mukerji et al. 2015), while another reported no significant changes in PEFR or predicted FEV1 at the same dosage (Solooki et al. 2014). Neither study observed a reduction in hospital stay length. Another study specifically explored the broncho-dilating effects of IV MgSO₄ in COPD exacerbations and its potential to enhance β2-agonist efficacy. While MgSO₄ alone did not significantly improve FEV1 compared to placebo, combining it with salbutamol produced a remarkable increase in bronchodilation. This suggests that MgSO₄ may amplify the effects of β2-agonists, possibly enhancing symptom relief and reducing hospital admissions during exacerbations (Abreu González et al. 2006). The reviewed studies utilized varying doses of MgSO₄, from 1.2 to 2.5 g, and had differing exclusion criteria, such as requirements for intubation, the presence of asthma, severe comorbidities, and hemodynamic instability. Standard treatments for COPD exacerbations, including antibiotics and corticosteroids, were inconsistently applied across studies. Although IV MgSO₄ shows promise as an adjunct therapy for acute COPD exacerbations, the current evidence remains limited, highlighting the need for larger, well-designed RCTs to confirm its efficacy and safety. Given the variability in study outcomes, identifying patient subgroups that may derive the most benefit from MgSO₄ is essential, as factors like disease severity, baseline lung function, and comorbid conditions, such as asthma, may influence effectiveness. Additionally, potential side effects—including reduced intercostal muscle strength and hypotension, particularly with rapid infusion—underscore the importance of careful dosing and monitoring in COPD management (Gottlieb et al. 2023). MgSO₄ and its versatility in anesthesia MgSO₄ has gained recognition as a versatile adjunct in anesthesia due to its wide-ranging effects, including enhanced neuromuscular relaxation, analgesia, cardiovascular stability, and organ protection (Dahake et al. 2024). MgSO₄ enhances neuromuscular blockade by blocking calcium channels at the presynaptic nerve terminal, which reduces acetylcholine release, resulting in effective muscle relaxation (Wang et al. 2011). This action reduces the need for nondepolarizing muscle relaxants, making MgSO₄ particularly useful for patients who may exhibit resistance to muscle relaxants, such as those with neuromuscular conditions like cerebral palsy (Do 2013). MgSO₄’s NMDA receptor antagonism provides analgesic benefits by preventing calcium influx in neurons, thereby reducing excitatory neurotransmission and pain perception (Gutiérrez-Román et al. 2022). This dual role of muscle relaxation and analgesia also allows for a reduced dose of primary anesthetics, such as sevoflurane and propofol, which can lower the risk of side effects related to these agents, including postoperative nausea and vomiting (Do 2013). MgSO₄ also exerts a stabilizing effect on the cardiovascular system by acting as a sympatholytic agent. Its capacity to lower systemic vascular resistance and prevent catecholamine release supports hemodynamic stability, particularly in high-stress situations like intubation and surgeries requiring controlled hypotension (James et al. 2018; Nakaigawa et al. 1997; Shimosawa et al. 2004). This effect is advantageous in surgeries, such as those involving the middle ear, where precise blood pressure control improves visibility in the surgical field. Additionally, MgSO₄’s neuroprotective and cardioprotective effects are crucial in specific procedures, including neurosurgery and cardiac surgery, as they help prevent excitotoxicity and stabilize myocardial function, respectively (Hallak et al. 2000; Li et al. 2007). In pediatric anesthesia, MgSO₄ shows potential benefits in reducing both postoperative emergence agitation and the incidence of laryngospasm, especially when administered locally. A recent meta-analysis demonstrated that perioperative MgSO₄ administration lowered laryngospasm rates by approximately 6%, with local (topical) application yielding a 12.5% reduction, particularly effective in adenotonsillectomy procedures (Rasheed et al. 2024). This suggests that MgSO₄’s efficacy may vary depending on the route of administration, with local applications near airway sites providing enhanced benefit. While generally well-tolerated, MgSO₄ can lead to adverse effects such as respiratory depression, hypotension, bradycardia, and muscle weakness when overdosed, underscoring the need for cautious administration, particularly in patients with cardiovascular or renal concerns (Dahake et al. 2024). Overall, MgSO₄’s range of applications in anesthesia—spanning muscle relaxation, analgesia, hemodynamic control, and airway protection—highlight its value in enhancing perioperative outcomes, especially in complex surgical cases and pediatric ENT procedures. MgSO₄ and the treatment of atrial fibrillation Atrial fibrillation (AFib) is a common arrhythmia characterized by an irregular and often rapid heartbeat originating in the upper chambers of the heart (atria). This irregular rhythm causes the atria to beat erratically, which can result in symptoms such as fatigue, palpitations, shortness of breath, dizziness, and lightheadedness. AFib is a significant risk factor for blood clots in the heart and, if untreated, can increase the probability of stroke. Contributing risk factors include high blood pressure, coronary artery disease, and obesity (Elsheikh et al. 2024). MgSO₄ has been considered a potential therapy for AFib due to its effects on myocardial potassium, calcium, and sodium channels, which help stabilize membrane potentials and may reduce AFib risk (Hoffer et al. 2022). While low serum magnesium levels have been associated with an increased incidence of AFib, studies on magnesium supplementation for AFib prevention and treatment have shown mixed outcomes (Bouida et al. 2019). A 2016 randomized controlled trial investigated the efficacy of MgSO₄ in atrial fibrillation management. The study found that while MgSO₄ did not significantly improve cardioversion success rates compared to placebo, it demonstrated potential as a valuable adjunct for rate control, particularly when combined with other agents such as digoxin (Kotecha 2016). This finding suggests that MgSO₄ may have a complementary role in atrial fibrillation treatment strategies, especially in scenarios where enhanced rate control is desired. In this context, IV MgSO₄ when used in addition to standard therapies was found to be effective for rate control in rapid AFib. It has been associated with a higher proportion of patients reaching target heart rates compared to standard therapies alone, and it has demonstrated moderate success in rhythm conversion to sinus rhythm, with evidence indicating that lower doses (5 g or less) may be more effective than higher doses (Enayati et al. 2023). Conversely, a study investigating MgSO₄ in acute AFib cardioversion has demonstrated that 40% of patients receiving MgSO₄ achieved spontaneous cardioversion, with an overall cardioversion rate of 85.6%. Additionally, MgSO₄ significantly reduced heart rate, a factor associated with symptom relief and predictive of successful cardioversion. As a membrane stabilizer, MgSO₄ may enhance sinus rhythm restoration and improve the efficacy of antiarrhythmic agents like flecainide, particularly in patients with minimal cardiac remodeling (Gilardi et al. 2022). In a multicenter, double-blind study, IV MgSO₄ was evaluated as an adjunct for AFib with rapid ventricular response (RVR) in an emergency department. The study found that MgSO₄ effectively lowered heart rate within the first 90 min compared to placebo; nonetheless, it did not meet primary endpoints for sustained rate reduction to below 100 bpm or a 20% reduction from baseline after 4 h (Nogic et al. 2022). While MgSO₄ reduced the need for additional beta-blockers for immediate heart rate control, no significant differences were observed in longer-term outcomes, such as hospital admission, length of stay, or 30-day mortality. Finally, a meta-analysis by Ramesh et al. (2021) evaluated the effects of IV MgSO₄ in rapid AFib management, analyzing six randomized controlled trials. The results indicated that IV MgSO₄ improved rate control in 63% of cases compared to 40% in standard treatment alone. MgSO₄ also facilitated sinus rhythm conversion in 21% of cases versus 14% with a placebo. IV MgSO₄ is generally well-tolerated, and adverse effects were minimal, with transient flushing being the most common. Although IV MgSO₄ shows promise as a complementary treatment for rapid atrial fibrillation control, additional research must address dosing parameters and clinical usage guidelines. MgSO₄ for management of chronic pain Pain is a complex sensation involving emotional, sensory, cognitive, and social elements, occurring from actual or potential tissue damage (Raja et al. 2020). It can be classified as acute or chronic and may be nociceptive, neuropathic, or inflammatory in origin (Treede et al. 2015). Chronic pain is defined as persistent discomfort lasting 3 months or more despite adequate treatment (Barroso et al. 2021), and it affects around 1.5 billion people globally, profoundly impacting both the quality of life and economic stability of the person (Park et al. 2020). The precise mechanisms underlying magnesium’s anti-nociceptive effects are not fully understood. However, it is known that magnesium blocks the ion channel of the NMDA receptor on postsynaptic spinal neurons in the dorsal horn (Na et al. 2011), preventing the influx of extracellular calcium ions and subsequent neuronal changes. This inhibition of calcium entry reduces central sensitization and produces analgesic effects. MgSO₄ shows potential in treating neuropathic pain, including postherpetic neuralgia, trigeminal neuralgia, and chemotherapy-induced neuropathy, particularly where traditional therapies may be less effective. MgSO₄ has also proven useful in decreasing postoperative opioid requirements and enhancing analgesia, especially during surgery or regional anesthesia. Additionally, it has shown efficacy in relieving pain associated with complex regional pain syndrome (CRPS), renal colic, headaches, and migraines (Soleimanpour et al. 2022). A recent narrative review assessed MgSO₄’s efficacy in chronic pain management across 33 studies, including 26 RCTs, indicated that IV magnesium is particularly effective for certain types of pain, with strong evidence supporting its use for renal colic and pelvic pain associated with endometriosis. However, evidence for its efficacy in other chronic pain conditions, such CRPS, neuropathic pain, chronic low back pain, and migraine prevention, remains limited or inconclusive (Onyeaka et al. 2024). Other studies by Urits et al. (2021) evaluated the effectiveness of MgSO₄, across various pain conditions, including CRPS, neuropathic pain, and abdominal pain, on multiple studies including RCTs, yielded mixed results. MgSO₄ showed significant pain reduction in conditions like CRPS, while it was less effective for general headache management. Notably, MgSO₄ demonstrated efficacy in migraine cases with aura, although its impact on general headaches was limited (Urits et al. 2021). Evidence for the use of IV MgSO₄ in managing CRPS remains inconclusive. A double-blind, placebo-controlled study on chronic CRPS type 1 showed no significant difference in pain reduction or functional impairment between MgSO₄ and placebo groups. However, MgSO₄ provided some benefits in patients with lower anxiety and depression scores, indicating the potential for targeted, patient-specific advantages (Fischer et al. 2013). In contrast, MgSO₄ has demonstrated significant benefits in managing postoperative pain following total knee arthroplasty (TKA). MgSO₄ administration demonstrated multiple beneficial outcomes in the postoperative period. Patients experienced superior pain control, evidenced by reduced pain scores both at rest and during movement in the first 48 h after surgery. This improved analgesia was reflected in decreased morphine consumption and extended intervals between analgesic doses. The enhanced pain management translated to improved functional outcomes, with patients achieving better knee range of motion and increased daily mobility starting from the first postoperative day. These benefits culminated in shorter hospital stays, suggesting that MgSO₄’s dual effect on pain reduction and opioid minimization facilitated accelerated recovery and earlier discharge (Wang et al. 2024). Another mechanism by which MgSO₄ modulates postoperative pain is through its anti-inflammatory effects. It reduces levels of interleukin-1β (IL-1β) and inducible nitric oxide synthase (iNOS), key markers of inflammation. Furthermore, MgSO₄ inhibits phosphorylation of the NMDA receptor NR1 subunit, a critical component in nociceptive signaling (Wen et al. 2024). Molecular mechanisms of action of MgSO4 at the cellular level MgSO4 exhibits complex molecular mechanisms of action that contribute to its therapeutic efficacy in various pathological conditions. Understanding these mechanisms is crucial for improving its clinical applications and developing enhanced therapeutic strategies. Membrane stabilization, ion channel modulation, and MgSO4 At the cellular membrane level, Mg2+ exerts multiple sophisticated effects that contribute substantially to its therapeutic actions through complex molecular mechanisms. Magnesium ions (Mg2⁺) play a critical role in modulating the structure and function of the plasma membrane through their interactions with the polar heads of phospholipids (Tocanne and Teissié 1990). The polar headgroups of phospholipids, such as phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), and phosphatidylinositol (PI), contain negatively charged phosphate groups (− PO₄⁻) and other polar moieties (e.g., carboxylates, hydroxyls, or amines). Mg2⁺, as a divalent cation, electrostatically binds to these negatively charged groups, particularly the phosphate and carboxylate groups, neutralizing their charge and reducing repulsion between adjacent phospholipid molecules (Hauser and Phillips 1979). This interaction stabilizes the membrane structure, enhances its rigidity, and reduces fluidity by restricting the movement of phospholipid headgroups. Mg2⁺ has a particularly high affinity for phosphatidylserine (PS), an anionic phospholipid predominantly located in the inner leaflet of the plasma membrane, and this binding is crucial for processes such as membrane fusion, apoptosis, and signal transduction (Lau et al. 1981; Martín-Molina et al. 2012). Additionally, Mg2⁺ influences the surface potential of the membrane, altering the distribution of other ions (e.g., Ca2⁺, K⁺, Na⁺) near the membrane surface and affecting ion channel activity and membrane protein function. By stabilizing the membrane, Mg2⁺ also plays a role in processes like vesicle formation, exocytosis, and endocytosis, where close apposition of membranes is required (Schultz et al. 2009). Furthermore, Mg2⁺ competes with other divalent cations, such as calcium (Ca2⁺), for binding sites on phospholipid headgroups, modulating membrane dynamics and signaling pathways (Hauser and Phillips 1979). These interactions are essential for maintaining membrane integrity, regulating cellular processes, and ensuring the proper function of membrane-associated proteins. Overall, Mg2⁺ acts as a key modulator of membrane properties, influencing its physical, chemical, and functional characteristics through its interactions with phospholipid headgroups (Bamgbose and Sharma 2016; Schultz et al. 2009). These membrane-protective properties are particularly crucial in pathological conditions characterized by increased oxidative stress, such as ischemia–reperfusion injury, inflammation, and various cardiovascular disorders (Bernardini et al. 2005; Ying et al. 2007). Under these challenging conditions, MgSO₄’s membrane-stabilizing effects help prevent cellular damage through multiple mechanisms: Reducing free radical access to membrane lipids by maintaining membrane structural integrity (Fernández et al. 2017, 2021). Preserving membrane-bound antioxidant systems by stabilizing the lipid environment around membrane-bound antioxidant enzymes (e.g., superoxide dismutase, catalase), maintaining the optimal conformation and function of these enzymes, and protecting these enzymes from oxidative damage and denaturation (Guzmán et al. 2023). Maintaining cellular calcium homeostasis by modulating calcium channel activity (Tang et al. 2018). MgSO₄’s ability to support membrane repair mechanisms while protecting essential membrane transport systems and preserving cellular signaling pathways makes it uniquely valuable in treating various pathological conditions. This comprehensive membrane protection, coupled with its role in maintaining cellular energy metabolism and preventing inflammatory mediator production, establishes MgSO₄ as a crucial therapeutic agent in conditions where membrane integrity and cellular function are compromised (Abad et al. 2015b; Chiarello et al. 2018; Fernández et al. 2017, 2021, 2024). Oxidative stress and MgSO4 Oxidative stress, characterized by an imbalance between ROS production and antioxidant defenses, plays a crucial role in numerous pathological conditions (Halliwell and Gutteridge 2015). MgSO4 has emerged as a crucial therapeutic agent in managing conditions characterized by oxidative stress. This simple inorganic salt demonstrates remarkable antioxidant properties through multiple mechanisms, making it particularly valuable in treating various pathological conditions where oxidative damage plays a significant role. At the cellular level, MgSO4 orchestrates a complex network of protective mechanisms against oxidative damage through multiple pathways and molecular interactions. Understanding these cellular responses provides crucial insights into the compound’s therapeutic potential (Abad et al. 2015b; Chiarello et al. 2018). MgSO4 plays a crucial role in cellular antioxidant defense through multiple interconnected mechanisms. Its action encompasses both direct antioxidant effects and the modulation of cellular antioxidant systems. As a direct antioxidant, MgSO4 participates in free radical scavenging, stabilizes cellular membranes, and prevents lipid peroxidation. The compound’s ability to protect membrane integrity is particularly significant, as it helps maintain cellular function under oxidative stress conditions. Moreover, MgSO4 exhibits substantial influence over enzymatic antioxidant systems, enhancing the activity and expression of key protective enzymes including superoxide dismutase (SOD), catalase, and components of the glutathione system (Ariza et al. 2005; Han et al. 2018; Wolf and Trapani 2008; Zheltova et al. 2016). The compound’s antioxidant properties extend to mitochondrial protection and cellular redox regulation. In mitochondria, MgSO4 helps maintain proper function by reducing ROS production, protecting the respiratory chain, and preventing permeability transition. Its influence on cellular redox status involves modulation of redox-sensitive pathways and enhancement of adaptive responses through transcriptional regulation, particularly via the Nrf2 pathway. The glutathione system is notably affected, with MgSO4 promoting both enhanced synthesis and improved recycling of this crucial antioxidant. These mechanisms collectively contribute to improved cellular resilience against oxidative stress, making MgSO4 particularly valuable in treating conditions characterized by increased oxidative damage. The compound’s multiple mechanisms of action in antioxidant protection, combined with its well-established safety profile, continue to make it an important therapeutic agent in clinical practice (Romani 2011; Ścibior et al. 2021; Yamanaka et al. 2016; Zheltova et al. 2016). In critical care settings, MgSO₄’s antioxidant properties demonstrate significant therapeutic value in managing acute conditions characterized by oxidative stress. This compound’s multifaceted actions make it a valuable tool across various medical conditions, particularly in respiratory, cardiovascular, and neurological emergencies: In cases of severe asthma, MgSO₄ exhibits a dual action as both a bronchodilator and antioxidant. This combination helps reduce airway inflammation and oxidative damage, providing rapid relief in acute exacerbations (Rowe et al. 2000). The bronchodilatory effect is primarily attributed to magnesium’s ability to relax smooth muscle cells, while its antioxidant properties help mitigate the oxidative stress associated with severe asthma attacks. The role of MgSO₄ in cardiovascular emergencies has proven effective due to its potential antioxidant effects on the myocardium. It is useful for treating torsade de pointes (a dangerous form of irregular heartbeat), managing digoxin-related heart rhythm problems, and treating severe ventricular arrhythmias (Antman 2002). In neurological emergencies, particularly subarachnoid hemorrhage and stroke, MgSO₄ has shown promise due to its ability to reduce oxidative stress-induced neuronal damage. Its use in these conditions potentially improves patient outcomes through multiple protective mechanisms (Muir and Lees 1995; van den Bergh et al. 2005). By addressing both the immediate neurological insult and the subsequent oxidative cascade, MgSO₄ offers a comprehensive approach to neuroprotection in acute settings. Recent clinical applications have expanded to include chronic conditions where oxidative stress plays a significant pathogenic role. In diabetic patients, MgSO4 supplementation has shown promise in reducing oxidative stress markers and improving endothelial function (Rezazadeh et al. 2021). The compound’s use in chronic respiratory conditions demonstrates benefits in reducing inflammation and oxidative damage to lung tissue (Rowe et al. 2000; Wongwaree and Daengsuwan 2022). Furthermore, emerging evidence suggests potential applications in age-related disorders and neurodegenerative conditions, where chronic oxidative stress contributes to disease progression (Xu et al. 2014). Current research employing cutting-edge molecular techniques and advanced analytical platforms continues to uncover fascinating dimensions of MgSO4’s antioxidant capabilities. High-resolution proteomics and metabolomics approaches have revealed that MgSO4 modulates multiple redox-sensitive pathways, including the Nrf2-ARE signaling axis, mitochondrial electron transport chain function, and cellular stress response mechanisms (Kawasaki et al. 2019; Reicher et al. 2022). MgSO4, cellular signaling, and gene expression mechanisms At the signaling level, MgSO₄ modulates several key pathways that play crucial roles in the pathophysiology and treatment of preeclampsia and related conditions. The compound significantly affects the MAPK cascades, including ERK1/2, p38 MAPK, and JNK pathways (Huang et al. 2015, 2010; Qi et al. 2020). In preeclampsia, ERK1/2 activation by MgSO₄ promotes trophoblast survival and enhances placental function, while p38 MAPK modulation reduces inflammatory responses in both the placenta and maternal vasculature. Additionally, JNK pathway regulation helps mitigate oxidative stress-induced damage in maternal and fetal tissues. MgSO₄ also inhibits the NF-κB signaling pathway, a key mediator of inflammation, thereby reducing placental inflammation and endothelial dysfunction in preeclampsia (Shi et al. 2020). This inhibition suppresses the expression of pro-inflammatory genes such as TNF-α, COX-2, and ICAM-1, which are typically elevated in preeclamptic placentas (Lu et al. 2018; Shi et al. 2020). Furthermore, MgSO₄ activates the Nrf2 pathway, a master regulator of antioxidant responses, enhancing antioxidant defenses in placental and vascular tissues. This activation is particularly crucial in combating the increased oxidative stress characteristic of preeclampsia. Collectively, these molecular mechanisms underscore the multifaceted action of MgSO₄ in addressing the complex pathophysiology of preeclampsia and related disorders, highlighting its importance as a therapeutic agent in obstetric care (Shi et al. 2020). MgSO₄ suppresses genes encoding pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) while enhancing the expression of anti-inflammatory factors (IL-10, TGF-β), promoting a more balanced inflammatory response in placental and immune cells (Sakowicz 2022; Sugimoto et al. 2012). MgSO₄ downregulates genes for adhesion molecules like VCAM-1 and E-selectin, reducing leukocyte adhesion and vascular inflammation in preeclampsia (Wang et al. 2022). It also modulates the expression of angiogenic factors such as VEGF and its receptors, potentially improving placental angiogenesis (Lecuyer et al. 2017). In trophoblasts and neurons, MgSO₄ upregulates antiapoptotic genes (e.g., Bcl-2) while downregulating proapoptotic genes (e.g., Bax), contributing to its neuroprotective effects in eclampsia and fetal neuroprotection (Ashique et al. 2023; Bagheri et al. 2019; Liu and Dudley 2020). The compound increases the expression of antioxidant enzymes (SOD, catalase, GPx) in various tissues, enhancing protection against oxidative damage. Additionally, MgSO₄ regulates the expression of calcium and magnesium channel genes, influencing vascular tone and neuromuscular excitability in eclampsia prevention. It also modulates energy metabolism and mitochondrial function genes, potentially improving cellular resilience in stressed tissues during preeclampsia (Mazur et al. 2007; Sugimoto et al. 2012; Wolf and Trapani 2008). These diverse effects on gene expression underscore MgSO₄’s multifaceted role in managing preeclampsia and related conditions, highlighting its importance in obstetric care. Understanding these pathways and gene expression changes helps develop more effective dosing regimens, identify relevant biomarkers, and predict treatment responses in preeclampsia, eclampsia, and other conditions where MgSO₄ is therapeutically beneficial. The comprehensive nature of MgSO₄’s effects on cellular signaling and gene expression underscores its value as a therapeutic agent in conditions characterized by oxidative stress and inflammation. MgSO4’s effects on mitochondrial function and energy metabolism The impact of MgSO4 on mitochondrial function and energy metabolism represents a crucial aspect of its therapeutic effects (Han et al. 2018; Huang et al. 2015; Mohammadi et al. 2020). At the bioenergetic level, MgSO4 plays a fundamental role in boosting ATP production through multiple mechanisms, including enhancement of ATP synthase activity, regulation of oxidative phosphorylation, and maintenance of the electron transport chain efficiency (Romani 2011). The compound’s ability to modulate electron transfer and reduce electron leakage not only improves energy production but also minimizes ROS generation, protecting mitochondrial integrity and function (Bernardini et al. 2005; Wolf and Trapani 2008). Mitochondrial membrane stability and calcium homeostasis are particularly influenced by MgSO4 (Chang et al. 2019; Mohammadi et al. 2020). Mg2+ helps maintain membrane potential and protects against permeability transition, while simultaneously regulating Ca2+ handling through modulation of uptake and efflux mechanisms. This dual action prevents Ca2+ overload and subsequent mitochondrial dysfunction, which is crucial in various pathological conditions. Furthermore, Mg2+ enhances mitochondrial quality control processes, including protein folding and repair systems, while regulating mitochondrial dynamics through fusion and fission events (Mohammadi et al. 2020; Wolf and Trapani 2008; Yamanaka et al. 2016). The antioxidant properties of MgSO4 extend to specific mitochondrial protection mechanisms. By upregulating mitochondrial antioxidant systems, including superoxide dismutase and the glutathione system, MgSO4 provides comprehensive protection against oxidative damage. This protection is particularly important for maintaining mitochondrial DNA integrity and preserving the function of essential mitochondrial proteins (Han et al. 2018; Mohammadi et al. 2020; Wolf and Trapani 2008; Yamanaka et al. 2016; Zheltova et al. 2016). A complex interplay between calcium homeostasis and MgSO₄ Magnesium plays a crucial role in regulating calcium levels in the body. When magnesium levels are too high (hypermagnesemia), blood calcium levels decrease. This may happen because excess magnesium interferes with how the body produces or releases parathyroid hormone (PTH) (Schumacher et al. 2021; Slatopolsky et al. 1976). When pregnant women are treated with MgSO₄, they sometimes develop low calcium levels (hypocalcemia) (Eisenbud and LoBue 1976; Monif and Savory 1972). On the other hand, when magnesium levels are slightly low, both calcium and PTH levels in the blood increase. However, severely low magnesium (hypomagnesemia) can cause calcium levels to drop. There is a complex two-way relationship between magnesium and PTH levels in the blood. While calcium levels are the main trigger for PTH release from the parathyroid glands, magnesium can similarly influence PTH secretion (Eisenbud and LoBue 1976; Monif and Savory 1972; Schumacher et al. 2021; Slatopolsky et al. 1976). Magnesium’s effect on PTH follows a paradoxical pattern: mild magnesium deficiency triggers increased PTH secretion, yet severe magnesium deficiency actually blocks PTH secretion, which can cause dangerously low calcium levels in patients. Recent research has revealed how this blocking effect works: severely low magnesium activates the alpha-subunits of heterotrimeric G-proteins. When activated, these proteins trick the parathyroid glands into behaving as if calcium levels are high (by mimicking the calcium-sensing receptor), which stops PTH production. This relationship works both ways—while magnesium affects PTH secretion, PTH also helps regulate magnesium levels in the body by controlling how much magnesium the kidneys reabsorb (Vetter and Lohse 2002). MgSO4 exerts its effects through multiple mechanisms, primarily through direct modulation of calcium channels and regulation of intracellular calcium management. At the molecular level, MgSO4 competitively inhibits calcium entry through voltage-gated channels, influences channel activation kinetics, and modifies channel conductance properties. This interaction extends to the regulation of calcium storage in the endoplasmic reticulum and mitochondrial calcium uptake, significantly impacting cellular calcium dynamics (Bara and Guiet-Bara 2001; Tang et al. 2018). In membrane systems, MgSO4 plays a crucial role in stabilizing membrane structure and regulating permeability, thereby protecting against calcium-induced damage (Chiarello et al. 2014). This membrane-stabilizing effect is particularly important in maintaining cellular integrity and function. The compound’s influence on calcium-dependent enzymes and second messenger systems further modulates cellular signaling pathways, affecting processes ranging from neurotransmitter release to muscle contraction (Abad et al. 2005a, 2015b; Chiarello et al. 2018). These mechanisms could contribute to MgSO4’s therapeutic efficacy in conditions such as preeclampsia, cardiac arrhythmias, and neurological protection. Understanding the complex interplay between calcium homeostasis and MgSO4 continues to inform therapeutic strategies, particularly in conditions where calcium dysregulation plays a pathological role. This knowledge has enabled the development of more effective treatment protocols and monitoring systems, while also suggesting new directions for research and clinical applications. The current investigation of these mechanisms promises to further enhance our ability to utilize MgSO4’s therapeutic potential in various medical conditions. Inflammatory response modulation by MgSO4 MgSO4 demonstrates potent anti-inflammatory properties through multiple molecular pathways and cellular mechanisms, making it a valuable therapeutic agent in various inflammatory conditions (Burd et al. 2010). At the cellular level, MgSO4 modulates immune cell function by regulating neutrophil activation and recruitment, reducing macrophage pro-inflammatory activity, controlling T-cell responses, and modifying dendritic cell function. It also significantly influences adhesion molecule expression, including ICAM-1, VCAM-1, and selectins, thereby affecting leukocyte-endothelial interactions and cell migration processes (Abbas and Sakr 2016). Furthermore, MgSO4 exhibits crucial control over oxidative burst mechanisms through the suppression of NADPH oxidase activity and regulation of ROS generation (Schreurs and Cipolla 2014). The molecular mechanisms underlying MgSO4’s anti-inflammatory effects involve several key signaling pathways (da Silva Lima et al. 2018; Sugimoto et al. 2012). It modulates the NF-κB pathway by inhibiting nuclear translocation and reducing IκB phosphorylation, thereby controlling inflammatory gene transcription (see the “MgSO4, cellular signaling, and gene expression mechanisms” section). MgSO4 also regulates the MAPK cascade, including p38 MAPK, ERK1/2, and JNK pathways, influencing cellular stress responses. A significant aspect of its anti-inflammatory action involves the regulation of cytokine networks, characterized by a reduction in pro-inflammatory mediators such as TNF-α, IL-1β, and IL-6 while enhancing anti-inflammatory factors like IL-10 and TGF-β (Orgul et al. 2021) (see the “MgSO4, cellular signaling, and gene expression mechanisms” section). This effect is particularly pronounced in response to lipopolysaccharide (LPS), a common inflammatory trigger (Suzuki-Kakisaka et al. 2013). MgSO₄ enhances immune tolerance to LPS by shifting the immune response toward an anti-inflammatory phenotype, as evidenced by the upregulation of CD163, a marker of M2 macrophage polarization (Chang et al. 2023). The effectiveness of MgSO₄ in inflammation reduction is dose-dependent (Ozen et al. 2020; Suzuki-Kakisaka et al. 2013). Higher concentrations, up to 10 mM, show enhanced efficacy in suppressing cytokine production and release, particularly IL-1β, during inflammatory conditions. However, excessive doses (100 mM) may induce apoptosis under non-inflammatory conditions, emphasizing the need for careful dosing to maximize therapeutic benefits while minimizing adverse effects (Ozen et al. 2020). MgSO₄ exerts its anti-inflammatory effects through the modulation of critical signaling pathways, including phosphoinositide 3-kinase (PI3K) and NF-κB (Chang et al. 2023). During acute inflammatory responses, MgSO₄ activates the PI3K pathway and inhibits NF-κB activation, thereby reducing inflammation. Interestingly, prolonged exposure to MgSO₄ results in the downregulation of both pathways, suggesting a dynamic and context-dependent role in inflammation modulation. These comprehensive effects make MgSO4 particularly valuable in treating various inflammatory conditions, from acute states like preeclampsia and acute asthma to chronic inflammatory disorders. Discoveries about MgSO4’s anti-inflammatory properties are emerging, enabling better treatment approaches and patient results in inflammatory conditions. Unveiling the role of MgSO4 as an antioxidant with computational chemistry Despite extensive evidence supporting the antioxidant properties of MgSO4 in diverse medical applications, the precise molecular pathway remains unclear. To bridge this knowledge gap in the molecular mechanisms behind the antioxidant capacity of MgSO4, our group has turned to advanced computational methods (Fernández et al. 2017, 2021, 2024). Employing techniques such as molecular dynamics (MD) simulations and quantum chemistry calculations has provided valuable insights into the potential molecular interactions and processes underlying the antioxidant effects of MgSO4. MD simulations elucidate the dynamic aspects of MgSO4 antioxidant activity, including its interactions with cellular membranes, influence on ion channel function, and effects on local water structure and dynamics. Conversely, advanced quantum chemistry calculations, including density functional theory (DFT) and ab initio methods, provide detailed insights into the electronic structure of MgSO4 and its interactions with ROS. These computational approaches reveal how MgSO4 influences electron transfer processes, stabilizes molecular orbitals, and modulates reaction energetics in biological systems. Therefore, these tools offer a promising avenue for unraveling the complex molecular mechanisms at play, complementing experimental findings and paving the way for a more comprehensive understanding of MgSO4 antioxidant properties. The association equilibrium of MgSO4 in aqueous solution may play a crucial role in understanding its antioxidant properties at the molecular level. Atkinson and Petrucci’s ultrasonic absorption studies confirmed that the ion pair (IP) formation follows a three-step mechanism, known as the Eigen mechanism (Atkinson and Petrucci 1966). This process can be described as follows: In this mechanism, the contact ion pair (CIP) of [MgSO4], where a Mg-O-S bond exists, interacts with water molecules (W) in a gradual process to form a solvent-shared ion pair (SIP) [Mg(W)SO4], where a water molecule comes between the ions. Subsequently, an ion pair separated by two solvent molecules (2SIP) [Mg(WW)SO4] is generated. Finally, this process culminates in complete dissociation, producing free ions in an aqueous solution (Mg2+(aq) + SO42−(aq)). This description details the transition from a CIP to fully solvated ions, passing through intermediate states of hydration, illustrating the process of gradual dissociation of MgSO4. The integration of computational insights with experimental data strengthens our understanding of MgSO4 therapeutic mechanisms and guides the development of optimized treatment strategies. Current challenges include the computational cost of quantum calculations, the accuracy of force fields for modeling ion-protein interactions, and the complexity of simulating long-timescale biological processes. However, ongoing technological advances and methodological improvements continue to enhance our ability to model and predict MgSO4 antioxidant effects at multiple biological scales. Effect of MgSO4 on pristine and oxidized lipid bilayer models with MD Lipid peroxidation (LP) is a chain reaction mechanism via free radicals that alter the physiological functions of the cell membranes. This generates many changes in the membranes emphasizing the loss of permeability through pore formation and continuous oxidation potentially leading to membrane disruption. It has been established that these changes in the membrane result from alterations in the conformational dynamics of the aliphatic chains modified by oxidation (Volinsky and Kinnunen 2013). Several studies conducted with MD have demonstrated the modifications in lipid bilayer models produced by the incorporation of oxidized lipids (Boonnoy et al. 2015; Oliveira et al. 2019; Sadžak et al. 2023; Wiczew et al. 2021). A typical example is given by Boonoy et al. (Boonnoy et al. 2015) who presented a simulation for palmitoyl-linoleoyl-phosphatidylcholine (PLPC) lipid bilayers with oxide versions in the form of hydroperoxide and aldehyde. They showed that the oxidized groups bend towards the interface with water increasing the area per lipid, decreasing the membrane thickness, decreasing the aliphatic chain order parameter, and increasing the water permeability. A stable pore is formed at medium concentrations of aldehydes due to the high mobility of the oxidized tail. Oliveira et al. (2019) evaluated the mechanical stress on oxidized lipid bilayers. Palmitoyl-oleoyl-phosphatidylcholine (POPC) bilayers, as well as bilayers with one of the oxidized forms, alcohol, hydroperoxide, and ketone, were subjected to uniform stretching until the pore formation. They found that the time needed to break the bilayer was shorter for the systems with hydroperoxide and alcohol compared to the normal bilayer. They also determined that areal strain, which refers to the change in critical area before rupture, was greater for the POPC bilayer than for the alcohol and hydroperoxide ones, i.e., oxidized lipid bilayers have a lower resistance to deformation caused by mechanical stress. Another study is given by Sadžak et al. (2023) where the effect of dicarboxylic acids, a by-product of LP, in a lipid bilayer was assessed. Simulations of dioleoyl-phosphatidylcholine (DOPC) bilayers with dodecanedioic acid revealed the formation of aggregates extending over the hydrophobic region which causes water penetration and the formation of water wires. Furthermore, the interaction of the dodecanedioic acid with the lipid polar heads buries them in the bilayer, confirming the detrimental effects of dicarboxylic acids on the membrane surface by increasing the roughness of lipid bilayer. The presented studies have shown some of the changes that lipid bilayers may undergo due to the incorporation of oxidized lipids, implying possible alterations suffered over cell membranes by LP. In this regard, in a previous study, the role of MgSO4 in the inhibition of lipid peroxidation initiated by ●OH was evaluated (Fernández et al. 2017). Simulations of POPC bilayers with ●OH radicals and MgSO4 were performed to study the effects of this species on membrane properties. The results showed a good agreement with experimental and MD calculations reports (Piggot et al. 2012). The ●OH distribution shows that this species does not cross the hydrophobic zone, but moves freely in water and is mainly located in the lipid ester group zone of the bilayer, which is in agreement with the literature (Cordeiro 2014). MgSO4 increases the membrane thickness, reduces the area per lipid, and increases the resistance to compression. The salt forms a PIC that is adsorbed over the membrane surface with the Mg2+ and SO42− close to the phosphate and choline groups, respectively. However, the resulting interaction between the MgSO4 and the radical is relatively weak with the ●OH approaching the Mg second solvation sphere (~ 4.5 Å). In this context, it demonstrates that MgSO4 can reduce the probability of ●OH interacting with the unsaturated lipid chains because the lipid bilayer is more compact. In a subsequent study, the effect of MgSO4 over an oxidized lipid bilayer model was evaluated (Fernández et al. 2021). In this opportunity, simulations of POPC bilayers with different concentrations of the oxidized forms, hydroperoxide and aldehyde, were conducted with the absence and presence of MgSO4. The results of the membrane properties for oxidized systems are in agreement with those reported in the literature (Kumar et al. 2018; Siani et al. 2016; Weber et al. 2014; Wong-ekkabut et al. 2007). In general, as the bilayers are more oxidized, the bilayer thickness decreases, the area per lipid increases, and the compressibility modulus decreases, highlighting the high mobility of the –CHO group. The addition of MgSO4 partially restores the membrane properties at a low oxidation level, emphasizing that the mobility of the –CHO groups is reduced, and their distribution is restricted to the interior of the bilayer. It is also found that the adsorbed MgSO4 will produce an increased interaction between lipid head groups due to the long-distance electrostatic between the Mg2+ and SO42− ions with oxidized groups. This suggests a screening of the surface negative and positive charges by Mg2+ and SO42− ions, respectively, lessening oxidative effects on the membrane. In this way, considering the low levels of membrane oxidation in various pathologies (Schumann-Gillett and O’Mara 2019), the MgSO4 should inhibit the membrane disruption by preventing the pore formation mitigating the oxidative effects. The role of MgSO4 in mitigating ●OH oxidation: an electronic structure analysis LP can be initiated by various external sources (air pollution, smoking, UV light, or ionization radiation) or endogenous (NADPH oxidase, xanthine oxidase, and uncoupled nitric oxide synthase) as well as leaks in the electron transport chain and the free Fe that may be generated (Yin et al. 2011). All these sources produce free radicals and ROS which aim lipids as their primary reaction target. Among the ROS present in living organisms, the ●OH stands out. This radical is the most reactive radical known to be associated with biological systems (Halliwell and Gutteridge 2015). It has a highly positive reduction potential, reacts rapidly with most biomolecules and organic molecules, and can abstract H from neighboring waters, spreading rapidly in aqueous solution. In an initial study, the role of this salt in the inhibition of LP initiated by ●OH was proposed (Fernández et al. 2017). Calculations for systems with MgSO4, ●OH, and nH2O molecules were carried out to analyze the ●OH–Mg interactions in a vacuum with several levels of theory. The results for the non-hydrated MgSO4 system compare well with those reported in the literature (Iype et al. 2012), and an important interaction for MgSO4-●OH system rising to − 74 kcal/mol is observed. For the hydrated [MgSO4(H2O)5] system, the distances are in agreement with theoretical (Iype et al. 2012; Zhang et al. 2002) and experimental (Cao et al. 2011) report, and a considerable interaction with ●OH is still observed in the [MgSO4(H2O)4●OH] system, confirming a strong interaction between MgSO4 and ●OH. The ●OH charge increases with spin density disappears and decreases the charge and a spin density of ~ 0.5 in the terminal oxygen atoms of SO42−. In this way, the radical is stabilized by the resonance effects on the two SO42− oxygen atoms due to the interaction with Mg, reducing their reactivity. Therefore, considering the rapid reactive diffusion of ●OH in water (Iglev et al. 2011), a hydrogen abstraction of a Mg coordination water by ●OH is proposed, where the spin density is simultaneously transferred to the SO42− oxygen atoms as HO●···H-OH-Mg-SO4 → HO-H···●OH-Mg-SO4. In this way, the adsorbed MgSO4 plays the role of an antioxidant by catching ●OH prior starting the LP, thereby preventing the cell membrane oxidation. More details about this electron transfer were performed in a recent study by Fernández et al. (2024), which showed the interaction of ●OH with different hydrated models of MgSO4. In this opportunity, 12H2O molecules were used to represent all three ion pairs (PIC, PIS, and 2PIS) in conjunction with the implicit solvation, necessary to improve the ion pair representation of this salt (Fernández et al. 2018). As a result, the ●OH − Mg interaction generated a spin-electron transfer from the sulfate to the ●OH, where a negative charge appears on ●OH and it is transformed into OH¯, and the charge on the sulfate decreases by half forming SO4●− for all ion pairs. It was also found that there is a spin density shift from OH to sulfate without the OH being directly coordinated to Mg, and the exchange of a Mg-coordinated water by the OH− further stabilizes the radical produced by the increase of electrostatic attractive interactions between Mg2+ with OH− due to the short Mg–OH distance and the decrease electronic repulsion within the sulfate. Taking into account these findings, a new scheme for the antioxidant mechanism of MgSO4 ion pairs was proposed. The approach of ●OH to a water molecule in the coordination sphere of Mg causes a spin-electron transfer from sulfate to OH, even at long distances of up to 10 Å, followed by a proton transfer from this H2O to form a OH− attached to Mg. The spin-electron transport can be modulated by the electric field of two charges of magnitude − 2e and + 2e between the ionic pairs of Mg2+–SO42¯ guiding spin-electrons transfer over long distances. This interaction stabilizes the radical for the conformations in which the OH− is outside the Mg2+ solvation sphere because the Mg − OH bond is stronger than Mg − OH2. A schematic of this process is shown in Fig. 1. In this regard, the antioxidant properties of MgSO4 can be attributed to the stabilization of the new radial located on sulfate by electron spin delocalization by resonance with an equally distributed spin density on the oxygen atoms and electrostatic stabilization, especially in the SIP and 2SIP conformations. Note that these ion pairs are often found in therapeutic low concentrations of this salt. (Connolly and Worthley 1999). A recent publication by Fernández et al. (2025) provides deeper insights into the electron transfer mechanisms of MgSO₄ with different hydrated models and ●OH, focusing on molecular orbital interactions. The study revealed a SOMO-HOMO (single- and highest-occupied molecular orbital) inversion for the ●OH radical, which subsequently shifts to the sulfate following spin-electron transfer. This phenomenon, previously observed in various inorganic and organic radical systems (Abella et al. 2021; Kasemthaveechok et al. 2022), is characterized by the SOMO orbital energetically positioned below the double-occupied HOMO orbital. The antioxidant activity of MgSO₄ is attributed to two factors: the enhanced stability of the newly formed radical on the sulfate, as mentioned earlier, and the formation of a bonding orbital between these oxygens, as evidenced by natural bond orbital (NBO) analysis. These findings significantly contribute to our understanding of MgSO₄’s molecular behavior and its antioxidant properties. These results are supported by experimental findings in which SO4●−shows higher selectivity and longer half-life time (30–40 μs) in water compared with ●OH (~ 10−3 μs) (Avetta et al. 2015). In this direction, SO4●− has shown a lower reactivity to natural organic molecules than ●OH, with a preference for electron transfer reactions (Zhang et al. 2021). In this regard, other theoretical studies have investigated the reactivity of SO4●− and ●OH with organic molecules. Liu et al. (2019) evaluated the decomposition of anthracene and oxygenated derivatives by SO4●− and ●OH using DFT. They found that both radicals play important roles in the initiation of anthracene and anthrone, highlighting that the reaction barrier is about one-third for ●OH than SO4●−. They also pointed out that the barriers for anthraquinone and 1-hydroxylanthraquinone are significantly higher for SO4●−, making ●OH being more relevant in the degradation of these species. Another study is given by Zhang et al. (2023) where DFT is used to determine the reaction mechanism of caffeine degradation with ●OH and SO4●−. They determine that both radicals can form radical adducts. Although, single electron transfer is preferred for SO4●−, while ●OH is favorable for the hydrogen atom abstraction route. Broader implications of the antioxidant mechanisms of MgSO₄ The antioxidant properties of MgSO₄ have significant implications for conditions characterized by oxidative stress, such as ischemia–reperfusion injury. During ischemia–reperfusion, the restoration of blood flow leads to a burst of ROS, including ●OH, which damages cellular membranes and organelles. By stabilizing ●OH and reducing its reactivity, MgSO₄ can prevent LP and maintain membrane integrity, thereby mitigating tissue damage. Moreover, MgSO₄’s ability to compact lipid bilayers and reduce pore formation is particularly relevant in IRI, where membrane disruption contributes to cell death and organ dysfunction. The partial restoration of membrane properties by MgSO₄ at low oxidation levels suggests its potential as a therapeutic agent in early-stage oxidative stress, such as that observed in IRI and neurodegenerative diseases. In summary, the molecular mechanisms underlying MgSO₄’s antioxidant activity—ranging from membrane stabilization to radical neutralization—highlight its potential applicability in various pathological conditions. Future studies should explore the therapeutic efficacy of MgSO₄ in vivo, particularly in models of ischemia–reperfusion and other oxidative stress-related disorders, to validate these findings and translate them into clinical applications. Future perspectives The future of MgSO4 research and applications presents exciting opportunities for advancement in both scientific understanding and clinical practice. Emerging research areas focus on identifying novel molecular targets, including new signaling pathways, receptor interactions, and epigenetic modifications that may explain MgSO4’s therapeutic effects. Advanced delivery systems, including nanoparticle-based platforms and targeted cellular delivery mechanisms, promise to enhance the compound’s efficacy while minimizing side effects. Developing precision dosing strategies and patient-specific protocols, supported by sophisticated response prediction models, will enable more personalized therapeutic approaches. Technological advancements are driving innovation in MgSO4 research and clinical applications. Real-time monitoring systems, point-of-care devices, and advanced molecular sensing technologies are revolutionizing how we track treatment responses and patient outcomes. The integration of artificial intelligence and machine learning algorithms with systems biology approaches is enhancing our ability to predict treatment outcomes and optimize therapeutic protocols. These developments are complemented by advances in analytical methods, including high-throughput screening, advanced proteomics, and metabolomic profiling, which provide deeper insights into MgSO4’s mechanisms of action. The emergence of personalized medicine approaches, supported by genetic profiling and biomarker-guided therapy, suggests a future where MgSO4 treatment can be precisely tailored to individual patient needs. Additionally, developing novel pharmaceutical formulations and combination therapies opens new possibilities for expanding MgSO4’s therapeutic applications across various medical conditions. Molecular simulations have proven to be invaluable in elucidating how MgSO4 functions as an antioxidant at the molecular level. As technology advances, computational chemistry techniques are becoming increasingly sophisticated in studying these antioxidant mechanisms. The emergence of quantum computing holds promises for enhancing the precision and breadth of molecular simulations, while neural networks are improving our ability to make accurate predictions. Looking ahead, combining traditional approaches like computational chemistry and molecular dynamics with cutting-edge methods in quantum computing and machine learning could significantly advance our understanding of MgSO4’s antioxidant properties, potentially leading to expanded therapeutic uses in medicine. The continued evolution of MgSO4 applications faces both challenges and opportunities. While issues such as mechanism complexity, individual variability, and implementation barriers require attention, the potential for enhanced therapeutic efficacy and improved patient outcomes drives ongoing research and development. The future of MgSO4 therapy hinges on adopting advanced monitoring tools and comprehensive data management systems. This evolution, guided by cost-effectiveness and quality metrics, will ensure optimal patient care while maintaining healthcare system efficiency.

The authors thank the supercomputing infrastructure of the NLHPC (ECM-02), Chile, for the computational time that has been generously provided Author contribution RM, CA, DR, MF, and FR performed the literature search and wrote the review. Data availability No datasets were generated or analysed during the current study. Declarations Ethics approval Not applicable. Consent to participate All the authors gave their consent to participate in this review article. Consent for publication All the authors gave their consent to publish this review article. Competing interests The authors declare no competing interests. Footnotes Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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