Sepsis is a worldwide health concern characterized by life-threatening organ dysfunction triggered by a dysregulated host response to an infection (What is Sepsis? | Sepsis | CDC, n.d.; Seymour et al., 2016; Singer et al., 2016; Reinhart et al., 2017; Rhee et al., 2019; Dong et al., 2020; Dupuis et al., 2020). Recent data from the Centers for Disease Control and Prevention suggest that approximately 1.7 million adults in the United States are affected by sepsis yearly, with an estimated 350,000 deaths attributable to the condition (What is Sepsis? | Sepsis | CDC, n.d). Furthermore, studies have found that between 30-50% of hospital deaths are caused by sepsis (What is Sepsis? | Sepsis | CDC, n.d.; Rhee et al., 2019). The prevailing circumstances are notably exacerbated in low- and middle-income countries, where the occurrence and death rate of sepsis are markedly greater, and also in the locations that have the least resources to prevent, detect, or treat sepsis ( Table 1 ) (Sepsis, n.d.; Rudd et al., 2020). Regardless of a country’s economic and healthcare status, sepsis remains a persistent and universal medical concern, as evidenced by the World Health Organization (WHO) designating sepsis as a global healthcare issue (https://www.who.int/news-room/fact-sheets/detail/sepsis) (Sepsis, n.d). It is crucial to evaluate and enforce stronger infection-prevention measures in regions with the highest sepsis rates, especially among vulnerable populations like neonates (Rudd et al., 2020). Numerous therapeutic improvement projects to treat sepsis have been launched in hospitals worldwide in response to the high incidence of sepsis and the belief that most sepsis-associated deaths are preventable with improved care. However, it is unlikely that better hospital-based care can prevent the majority of sepsis-associated deaths. Additional advancements in the prevention and management of underlying conditions may be required to significantly decrease mortality rates associated with sepsis (Rhee et al., 2019). Though sepsis is a multifaceted physiological response to infection that affects the entire organism causing organ dysfunction, septic shock is a “subset of sepsis characterized by severe circulatory, cellular, and metabolic abnormalities that pose a higher risk of mortality compared to sepsis alone” (Tanaka et al., 2000; Singer et al., 2016). The most severe cases tend to exhibit elevated levels of plasma glucose (Freire Jorge et al., 2017), triglycerides (Lee et al., 2015), and lactate (Nichol et al., 2010; Casserly et al., 2015; Shankar-Hari et al., 2016), while hypoglycemia in combination with hyperlactatemia has been associated with increased incidences of renal and liver dysfunction and mortality (Freire Jorge et al., 2017). Multiple processes, including hypoxia and oxidative stress (OS), contribute to sepsis, characterized by systemic inflammation in response to bacterial infection.

Despite the advancement of our knowledge of sepsis and improved therapeutic modalities, septic shock remains a significant contributor to mortality in intensive care units (ICUs) (Basodan et al., 2022). Though extensive therapeutic studies have been conducted on animals, the results have yet to be successfully translated into human therapeutic practice. There are obvious distinctions between animal models of disease and what is seen in human patients, and it is well-acknowledged that no “one-animal model” can recreate the complex and variable clinical presentations of sepsis syndrome (Nandi et al., 2020). Nevertheless, these studies possess scientific significance in comprehending the fundamental pathophysiology and verifying innovative therapeutic and diagnostic methods, provided that a thorough assessment of the potential risks and benefits has been undertaken and the data is interpreted realistically.

Sepsis is characterized by an exaggerated and imbalanced immune response triggered by an infection. Typically, the course of an infection entails a regulated inflammatory cascade that transpires via the delicate equilibrium between pro- and anti-inflammatory molecules (Esposito et al., 2017). In instances where sepsis remains unregulated, a series of subsequent occurrences may transpire, ultimately leading to the development of septic shock and multi-organ failure (Chiu and Legrand, 2021). Many pathophysiological pathways, including sepsis, inflammation, and organ disorders, have been linked to OS (Abelli et al., 2022). The current review article aims to present a comprehensive overview of the cellular metabolism of reactive oxygen species (ROS) and its involvement in pathophysiological processes, particularly in sepsis. This review article also offers a thorough overview of the potential use of antioxidants specifically with antimicrobial properties, as a supplementary treatment for sepsis, in addition to primary therapies such as fluid and antibiotic therapies. Additionally, the available antioxidants and the potential reasons for their effectiveness or lack thereof in mitigating diseases caused by OS are discussed, along with recent advancements in mitochondria-targeted antioxidants and their potential implications, as well as multi-antioxidant therapy and immunoadjuvant therapy.

While OS refers to an imbalance between oxidants and antioxidants, favoring the oxidants, this imbalance consequently disrupts redox signaling and regulation and can potentially cause harm at the molecular level. While oxidative eustress refers to a low-level (physiological) OS that plays a role in redox signaling and regulation, oxidative distress refers to a supraphysiological oxidative challenge that results in impaired redox signaling and/or oxidative damage to biomolecules (Sies, 2019) ( Figure 2 ). The significance of ROS in serving as signaling molecules for the facilitation of regular cellular processes and the ability to adapt to cellular stress cannot be ignored. One of these adaptations is the response to infection, both a cause and a consequence of critical illness. The regulation of ROS has the potential to modulate the extent of the inflammatory response.

Sepsis is a complex syndrome with multiple contributing factors. As a life-threatening complication caused by OS and inflammatory reactions, it represents a leading contributor to mortality in critically ill individuals. Several molecular mechanisms underlying the progression of sepsis are associated with the dysregulation between the generation of ROS and its elimination through cellular antioxidant pathways (Abelli et al., 2022). In sepsis, excessive generation of oxygen free radicals contributes to the development of multiple organ failure and mortality (Cowley et al., 1996).

The pathogenesis of sepsis encompasses infection by gram-positive and gram-negative bacteria, fungi, or a combination thereof. Sepsis is characterized by an intensified inflammatory response and in severe cases, hypotension, vasodilatory shock, and reduced oxygen delivery to tissues can occur due to cellular impairment of oxygen utilization. Though ROS and reactive nitrogen species (RNS) are involved in the progression of sepsis, their precise significance and function remain unclear. However, hyperpermeability, hypotension resulting from decreased vascular resistance, and mitochondrial dysfunction in respiration are crucial factors contributing to multiorgan failure and, ultimately, fatality in individuals with sepsis. The involvement of ROS/RNS, namely superoxide (O₂−), hydroxyl radical (^•OH), hydrogen peroxide (H₂O₂), nitric oxide (NO^•), and peroxynitrite (ONOO−), has been documented as one of the underlying mechanisms of these effects. The impairment of mitochondrial function is linked with depletion of the inner membrane and the hindrance of the electron transfer chain and FoF1-adenosine triphosphate-synthase within the mitochondria, leading to decreased cellular energy production. Furthermore, the excessive generation of NO^• resulting from inducible nitric oxide synthase (iNOS) activity is linked to detrimental consequences such as widespread vasodilation and reduced sensitivity to exogenously administered vasopressors (Prauchner, 2017). Sepsis is characterized by the induction of iNOS production in diverse cells due to the action of inflammatory mediators and cytokines.

Several studies on sepsis have demonstrated the presence of oxidative imbalance and increased OS due to a combination of factors, including hypotension, microvascular thrombosis, mitochondrial damage from OS, and other mechanisms, such as inflammation (Angus and van der Poll, 2013). An investigation by Takeda et al. observed that septic patients exhibited elevated levels of thiobarbituric acid reactive substance (TBARS), indicating a rise in lipid peroxidation (LPx) (Takeda et al., 1984). A reduction in the levels of antioxidants was also observed (Goode et al., 1995). According to Cowley et al., individuals who survived sepsis exhibited higher levels of antioxidant potential than those who did not (Cowley et al., 1996). Additionally, the antioxidant potential was observed to increase rapidly and reach normal or supranormal levels. Two additional prospective observational studies have demonstrated a correlation between total antioxidant capacity and the Acute Physiology and Chronic Health Evaluation II (APACHE II) score (Chuang et al., 2006), as well as a correlation between antioxidant deficiency and mortality (Karapetsa et al., 2013). Survival was associated with stronger catalase (CAT) activity, lower protein carbonyl (PC) levels, and stable glutathione (GSH) levels in erythrocytes. A study has reported a significant decrease in plasma vitamin C levels among individuals diagnosed with multiorgan failure (Borrelli et al., 1996). The deleterious effects of increased levels of oxidants in sepsis involve the alteration of proteins, lipids, and nucleic acids, which subsequently results in cellular damage and impaired endothelial function. Furthermore, the deterioration of glycocalyx and intercellular junctions among endothelial cells results in increased vascular permeability, a fundamental aspect in the progression of sepsis (Rubio-Gayosso et al., 2006).

Activation of nuclear factor kappa B and treatment with lipopolysaccharide (LPS) increase inducible nitric oxide synthase (iNOS) activity, leading to increased levels of nitric oxide (NO) that can react with superoxide anions to generate ONOO− (Brown, 2001). A similar correlation between OS and mortality in sepsis has been observed between the SOD: CAT ratio. Manganese-containing superoxide dismutase (Mn-SOD) typically converts superoxide to H₂O₂; subsequently, CAT converts H₂O₂ to water. However, the quantities of these enzymes vary under conditions of high OS, such as sepsis, which may lead to an accumulation of harmful ROS (Andrades et al., 2005).

Clinical oxidative indicators that can detect the byproducts of ROS damage to membrane lipids, proteins, and nuclear components include measurement of malondialdehyde (MDA), F2-isoprostanes, and 8-hydroxy-2’-deoxyguanosine (Sahoo and Chainy, 2023). Endogenous antioxidant enzymes, including CAT, SOD, and glutathione peroxidases (GPx), also serve as important biomarkers of OS. Another indicator is the ratio of reduced to oxidized thiols. Electrochemical measuring of derived reactive oxygen metabolites (dROM) (d-ROM, an index of OS) or biological antioxidant potential (BAP) or the redox balance (d-ROM/BAP ratio) is now possible because of recent technological advancements (Cortese-Krott et al., 2017; Araki et al., 2018; Miripour et al., 2022). Point-of-care (POC) systems have made it possible to quickly assess OS levels with a minimal blood sample (Cortese-Krott et al., 2017; Araki et al., 2018; Miripour et al., 2022).

Using a porcine model examining the alterations in the plasma proteome associated with sepsis revealed that there were changes in the plasma levels of 36 proteins, with 30 proteins being upregulated and 6 proteins being downregulated. These proteins represent a total of 27 unique proteins, as determined by differential proteomics and include CD14, haptoglobin and haemopexin (Thongboonkerd et al., 2009). CD14 is linked to acute-phase reaction proteins and OS pathways, whereas hemopexin acts as both an anti-inflammatory agent and oxidative scavenger.

The receptor for bacterial lipopolysaccharide (LPS) is CD14, which works together with TLR4 and MD-2 to activate the innate immune response ( Figure 1 ) (Frantz et al., 2007; Sahoo et al., 2022). Haptoglobin is an acute-phase reaction protein that binds to hemoglobin, preventing renal iron loss and oxidative damage caused by free hemoglobin (Lim et al., 2000; Van Campenhout et al., 2006). Hemopexin is responsible for binding to heme and facilitating its transportation to the liver, where it undergoes breakdown and enables the recovery of iron. Elevated levels of hemopexin, an anti-inflammatory molecule and oxidative scavenger, were observed during the early stages of sepsis, as heme is known to be highly toxic to cells due to its pro-inflammatory and oxidative effects (Van Campenhout et al., 2006; Thongboonkerd et al., 2009). The High-mobility group box 1 (HMGB1) protein, a nuclear chromatin-binding protein associated with damage-associated molecular patterns (DAMPs), also plays a crucial role in OS regulation and subsequent cellular processes such as apoptosis (Tang et al., 2011). Additionally, HMGB1 plays a crucial role in mediating delayed endotoxin lethality and is indispensable for the complete manifestation of inflammation in animal models of endotoxemia, sepsis, and arthritis. The efficacy of administering HMGB1 blockade after a delay of up to 24 hours following the initiation of experimental sepsis presents a distinctive temporal window that affords potential for rescuing individuals from fatal septic conditions (Andersson and Tracey, 2003).

As organoids offer numerous advantages over conventional models and have been extensively utilized in both fundamental and clinical research (Kopper et al., 2021; Minkler et al., 2021; Bedos et al., 2022; Gabriel et al., 2022a; Gabriel et al., 2022b; Moshksayan et al., 2023; Sahoo et al., 2023b; Gabriel et al., 2024), there are also reports using renal and intestinal organoids in sepsis. The use of organoids pre-treated with LPS serves as an effective means to study the impact of LPS-induced intestinal injury, which closely resembles sepsis, and facilitates the investigation of immune-associated mechanisms as well as the screening of potential therapeutic agents (Huang et al., 2022). Kidney organoids derived from human pluripotent stem cells (hPSCs) were used to investigate the effects of methylprednisolone (MP), a synthetic corticosteroid, on LPS-induced OS and injury. LPS is commonly used to simulate sepsis-associated acute kidney injury (SA-AKI) in both in vivo and in vitro models (Zhang W. et al., 2021). The results showed that MP partially alleviated the injury by reducing OS (by lowering induced MDA content and myeloperoxidase (MPO) expression and increasing SOD activity) and apoptosis in kidney cells (Zhang W. et al., 2021).

A contributing mechanism behind the pathophysiology of sepsis involves mitochondrial dysfunction, which generates significant levels of ROS which can result in cell death (e.g., mitoptosis) ( Figure 3 ) (Preau et al., 2021). By inducing mitochondrial decoupling, which in turn enhances harm from OS and sepsis, ROS and RNS exacerbate the damage in processes like sepsis. The pathogenesis of sepsis is attributed to an exaggerated immune and inflammatory reaction, marked by a substantial surge in ROS, nitric oxide (NO), and inflammatory cytokines. The overexpression of iNOS in sepsis may be inhibited by antioxidants, as nuclear factor-κB regulates iNOS expression and can be activated by ROS. Typically, intricate antioxidant defense mechanisms regulate OS in mitochondria through interdependent interactions. Sepsis results in a widespread impairment of the vascular endothelium, tissue function, and overall respiratory capacity. This is accompanied by a depletion of antioxidants and dysfunction in mitochondrial respiration, leading to reduced ATP and O₂ consumption levels.

The pathogenesis of sepsis-associated organ dysfunction is linked to oxidative damage to mitochondria. Diminished ATP levels expedite apoptosis and necrosis and are a contributing factor to multiple organ failure. In particular, mitochondrial cardiolipin peroxidation increases ROS generation via cytochrome c dissociation, leading to decreased ATP levels ( Figure 3 ) (Murphy, 2009). In addition, an oxidant environment can cause alterations in protein, lipid, and DNA structure, which in turn causes deficiency in ATP and further deterioration of homeostatic mechanisms (Rubio-Gayosso et al., 2006). Increased mitochondrial permeability is connected with mitochondrial dysfunction (Belikova et al., 2007). Sepsis leads to a reduction in the rates of mitochondrial state 3 respiration. Non-surviving septic patients exhibited lower ATP concentrations and ATP : ADP ratios compared to survivors (Brealey et al., 2002). Additionally, septic shock alters cytoplasmic glycolysis at the transcriptional level. For example, when healthy participants given intravenous endotoxin (Calvano et al., 2005), some of the most important metabolic enzymes involved in glycolysis and the mitochondrial respiratory chain (MRC) were found to be transiently under-expressed. Also, in the diaphragms of septic rats, transcription, synthesis, and activity of MRC components and the key enzyme of glycolysis, phosphofructokinase-1, were found to be downregulated (Callahan and Supinski, 2005). Moreover, in septic rat muscle, pyruvate dehydrogenase activity was reduced and its inhibitor, pyruvate dehydrogenase kinase activity, was increased, resulting in less pyruvate entering the mitochondria and more pyruvate being converted to lactate (Vary, 1996; Losser et al., 2010). Multiple investigations have shown that sepsis patients have cellular energy loss. In critically ill patients, this is linked to poorer outcomes, particularly mitochondrial dysfunction (Brown, 2001; Prauchner, 2017). This results in decreased levels of intracellular ATP leading to changes in Ca²⁺ homeostasis, further increase in ROS, and release of pro-apoptotic proteins. Concurrently, changes in mitochondrial permeability occur due to the correlation between matrix inflammation and respiratory chain uncoupling. The Ca²⁺ outflow, increased ROS production, membrane potential loss, and the release of cytochrome c from mitochondrial complexes occur within the mitochondria and contribute to cellular apoptosis ( Figure 3 ) (Kozlov et al., 2011). Ultimately, apoptosis and cytochrome c release can be triggered by disruption to the mitochondrial membrane ( Figure 3 ) (Galley, 2011). Another key player in the evolution of sepsis and OS is the family of NADPH oxidases (NOX). Seven different isoforms of NOX, each with its own unique catalytic domain, have been described. These include NOX1, NOX2, NOX3, NOX4, and NOX5 as well as Duox1 and Duox2. NOX4 is the most potent generator of ROS since it can be activated by various inflammatory stimuli such as LPS, tumor necrosis factor-alpha (TNF-α), TGF-β, and hypoxia (Pendyala et al., 2009).

Changes in cellular energy metabolism occur in sepsis due to disruptions in the mitochondrial electron transport and glycolytic pathways. Acute septic conditions are associated with changes in glucose metabolism that can be thought of as a “redistribution of glucose consumption away from mitochondrial oxidative phosphorylation” toward other metabolic pathways, including lactate generation. There appears to be no impact on cellular energy supply from this rerouting. This could be because the cells are consuming less ATP, which causes them to show signs of metabolic failure (Singer, 2005). The development and maintenance of sepsis-induced anomalies in cellular energy metabolism can be attributed to the decline in the expression of genes that encode crucial electron transport and glycolytic proteins (Callahan and Supinski, 2005). The mitochondrial respiratory chain (MRC) undergoes structural and functional changes during sepsis (Losser et al., 2010), with essential enzymes of electron transport and ATP production (Levy, 2007) and mitochondrial biogenesis (Haden et al., 2007) being inhibited. These findings were also observed in monocytes derived from patients in septic shock (Adrie et al., 2001) and skeletal muscle (Brealey et al., 2002). Sepsis results in the suppression of genes that encode components of the mitochondrial electron transport chain (ETC), including cytochrome-c oxidase 5A and the rate-limiting enzyme for glycolysis, phosphofructokinase (PFK). Peroxiredoxin-3 and thioredoxin reductase-2 enzymes, which are involved in the mitochondrial thioredoxin-2 (TRX-2) oxidation, are part of yet another antioxidant defense system. The TRX-2 system proteins exhibited greater resistance to OS and played a significant role in safeguarding against mitochondrial dysfunction under sepsis conditions in human endothelial cells in vitro studies (Galley, 2011), suggesting that the TRX-2 system plays a larger role in sepsis.

The involvement of mitochondrial OS in the development of organ dysfunction induced by sepsis has been established. In simulated sepsis conditions, the silent information regulator-1 (SIRT-1)-activator-3 (a selective synthetic agonist of SIRT-1) activation of the peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC1α) and nuclear factor erythroid 2-like 2 (NFE2L2) pathways demonstrated a protective effect on cells against LPS/PepG-induced loss of mitochondrial membrane potential and metabolic activity, as well as a reduction in interleukin-6 (IL-6) responses. Furthermore, there was an observed increase in mitochondrial biogenesis and glutathione (McCreath et al., 2016).

Both anti-inflammatory and pro-inflammatory cytokines are believed to have significant roles in sepsis pathogenesis. Septic individuals exhibited notable increases in plasma and/or serum concentrations of IL-6, interleukin-8 (IL-8), interleukin-10 (IL-10), interleukin-18 (IL-18), and TNF-α. The overproduction of IL-6, IL-8, IL-18, and TNF-α contributes to excessive inflammation, while IL-10 is involved in later immunosuppression (Chaudhry et al., 2013). Multiple studies have demonstrated a positive correlation between elevated plasma concentrations of IL-18 and unfavorable clinical prognosis in septic individuals (Tschoeke et al., 2006). Similarly, numerous reports note elevation in serum concentrations of IL-1β, IL-6, IL-8, and TNF-α between neonatal individuals with sepsis and the corresponding control cohorts. Subsequent antibiotic treatment resulted in a noteworthy reduction in the serum levels of these cytokines, underscoring the efficacy of antibiotic intervention in mitigating the inflammatory response associated with sepsis in neonates (Kurt et al., 2007). Conversely, the prediction of mortality at 28 days relied specifically on the utilization of IL-8 and MCP-1. The cytokines IL-8 and MCP-1 showed the most significant correlation with the sequential organ failure assessment (SOFA) scores in septic patients on the first day of observation.

Despite the development of new therapeutic agents, sepsis continues to exhibit high rates of morbidity and mortality; therefore, it is important to understand its pathogenesis in order to devise efficacious treatment modalities. For many years, it was believed that the pathophysiology of sepsis was associated with uncontrolled inflammation (i.e., cytokine storm) ( Figure 4 ), resulting in cardiovascular failure, organ failure, and mortality. There has been a significant increase in the testing of various therapeutic agents, such as tumor necrosis factor inhibitors, IL-1 blockers, and corticosteroids, in large-scale clinical trials, with the aim of targeting inflammation. No cytokine-targeting agents or anti-inflammatory treatments have demonstrated substantial efficacy, and certain interventions have led to higher mortality rates. Researchers have discovered that the inflammatory response profiles in individuals with sepsis are more intricate than initially believed (Hotchkiss et al., 2013). Research findings have demonstrated that there exists a significant suppression in the production of cytokines by splenocytes obtained postmortem from individuals who succumbed to sepsis. This suppression can be attributed to a phenomenon known as T-cell exhaustion, which is a recently acknowledged mechanism of immunosuppression that arises as a result of prolonged exposure to antigens (Hotchkiss et al., 2013).

Numerous clinical trials have been conducted to investigate the efficacy of TNF and interleukin 1 (IL-1) antagonists, toll receptor blockers, and endotoxin antagonists in the context of sepsis. The outcomes of over 30 trials involving a range of anticytokine and anti-inflammatory medications have consistently demonstrated a lack of favorable effects or, in certain instances, a decrease in survival rates. The findings collectively suggest that certain individuals afflicted with sepsis exhibit a rapid synthesis of both proinflammatory and anti-inflammatory cytokines, while others demonstrate an imbalance in favor of anti-inflammatory cytokines or a general suppression of cytokine production. Indeed, the precise etiology underlying mortality and organ dysfunction in the majority of septic patients remains elusive. Clinical trials place significant emphasis on the extent of immunosuppression observed in cases of sepsis while also elucidating the reasons behind the lack of success in numerous sepsis trials that focused on inhibiting inflammatory mediators or disrupting pathogen recognition signaling pathways. Also, the occurrence of sepsis elicits robust inflammatory responses, which in turn trigger alterations in gene expression through epigenetic mechanisms encompassing DNA methylation, histone modification, and chromatin remodeling. These processes are collectively responsible for inducing both upregulation and downregulation of gene activity. The findings from various studies suggest that there is a correlation between intense immunoinflammatory responses, such as sepsis, and the occurrence of epigenetic changes. These changes have been observed to lead to a disruption in the expression of genes responsible for regulating crucial immune activation responses and, consequently, rendering the host more vulnerable to infections. The salient observation persists that a considerable number of ICU patients fail to recover due to the persistence of an ongoing infection. Despite the administration of broad-spectrum antibiotics and the implementation of rigorous source control measures, a number of patients fail to completely eliminate their infections and subsequently experience the onset of secondary hospital-acquired infections (Otto et al., 2011; Kethireddy and Kumar, 2012). Hence, it can be postulated that therapeutic interventions aimed at enhancing immune competence may exert a profound impact on clinical outcomes, manifesting in expedited resolution of the primary infection and averted morbidity and mortality resulting from secondary infections of a fatal nature.

A body of evidence has substantiated the notion that a deficiency in micronutrients can cause a state of immune function suppression. This phenomenon exerts its influence on both the innate T-cell-mediated immune response and the adaptive antibody response, thereby inducing modifications to the equilibrium of the host’s response. The maintenance of an optimal immune system function appears to necessitate the consumption of a sufficient quantity of vitamins and antioxidant compounds (Mishra et al., 2023). The phenomenon of immunological alterations during the process of aging as a result of inadequate intake of essential micronutrients is well-documented. These alterations have been observed to occur with notable frequency and have been found to be closely linked to an increased vulnerability to various infectious agents. OS triggers inflammatory responses through the activation of redox pathways due to nuclear factor κB (NFκB) activation, leading to elevated levels of circulating inflammatory mediators such as cytokines and pentraxin-3 in sepsis patients (Arnalich et al., 2000; Galley, 2011).

While ROS are integral to cellular processes, especially those of immune cells, it is imperative to maintain sufficient levels of antioxidant defenses to counteract the deleterious consequences of excessive ROS generation. In addition to their role in generating ROS essential for microbicidal activity, immune cells exhibit susceptibility to exogenous ROS as a consequence of their elevated polyunsaturated fatty acids (PUFA) composition. Immune cells exhibit an atypical nature in comparison to other somatic cells due to their elevated concentrations of antioxidant vitamins. This characteristic is believed to confer a safeguard against LPx and immunosuppression, which are widely recognized hazards associated with increased PUFA levels (Bendich, 1988). The maintenance of an efficient immune response is facilitated by the presence of antioxidant vitamins and trace elements (Wintergerst et al., 2007). This was evident from a study in which the administration of a vitamin E supplement to a cohort of elderly healthy individuals resulted in an elevation in the antibody titer for both the hepatitis B and tetanus vaccines. Consequently, the supplementation led to an augmentation of T-cell-mediated functions (Simin Nikbin et al., 1997). The maintenance of sufficient levels of antioxidants may present a valuable strategy in mitigating cellular damage and impairment observed in select inflammatory and autoimmune conditions (De la Fuente, 2002; De La Fuente et al., 2005).

The impact of various therapeutic agents on the management of sepsis has been investigated. Antioxidant therapy is widely used in cases of OS damage. Antioxidants come in several forms, each with its own unique mechanism of action and clinical use (Sahoo et al., 2008b; Prauchner, 2017; Chainy and Sahoo, 2020; Toro-Pérez and Rodrigo, 2021; Ilango et al., 2022; Patani et al., 2023; Sahoo and Chainy, 2023; Sahoo et al., 2023a). Although oxidative damage is commonly observed in various organs during the progression of sepsis and there exists a direct association between oxidative markers and organ damage, the efficacy of antioxidant effects appears to be contingent not only on the reduction of oxidative damage but also on its anti-inflammatory properties.

The administration of antioxidants has effectively reversed organ failure in some murine sepsis models. This phenomenon can be attributed to the imbalance of antioxidant enzymes, infiltration of neutrophils, and the presence of OS. In one murine study, the group with cecal ligation and puncture (CLP) exhibited a positive correlation between the levels of TBARS and markers of organ injury in the lung and kidney. While the correlation between oxidative damage and an elevated SOD/CAT ratio was observed solely in the pulmonary system (Andrades et al., 2011), the correlation between MPO activity and oxidative damage was observed in the kidney but not in the lung, indicating that the origin of oxidative damage varies depending on the organ. These findings demonstrate variations in the impact of fundamental support and antioxidants on organ dysfunction subsequent to sepsis (Andrades et al., 2011).

Antioxidant nutrients, such as vitamins C and E, β-carotene, selenium, iron, copper, and zinc, are frequently incorporated into dietary regimens ( Table 2 ). These nutrients enhance diverse immune functions, thereby playing a significant protective role against infections instigated by bacteria, viruses, or parasites. Consequently, it is plausible that interventions aimed at bolstering host immunity could potentially augment survival rates (Puertollano et al., 2011). Moreover, during OS occurring in sepsis, three primary mechanisms play a pivotal role: vasomotor impairment, mitochondrial dysfunction, and necrosis in various tissues (Abelli et al., 2022). Hence, an overabundance of ROS gives rise to a disturbance in the physiological endothelial function, resulting in vasoplegia, an excessive procoagulant state induced by the inhibition of the ADAMTS-13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) enzyme, and impairment of mitochondrial integrity, thereby disturbing the signaling cascades governing thrombosis and inflammation (Dolmatova et al., 2021). There exist certain antioxidant molecules that possess the capability to selectively target and modulate the aforementioned reported mechanisms. Consistent with this notion, a variety of antioxidants, including polyphenols, β-glucan, vitamins C and E, melatonin, N-acetylcysteine, mitochondrion-targeted antioxidants (MitoQ, MitoVitE, and peptides linked to dimethyl tyrosine), selenium salts, and organoselenium compounds, have demonstrated efficacy in mitigating OS in animal models of sepsis, as well as in several clinical trials involving septic patients. However, it is essential to note that there have been studies on antioxidant therapies in which adverse effects have been observed (Jain and Chandel, 2013).

Some reports suggest that antioxidants can potentially interfere with the regular signaling mechanisms that regulate the response to severe infection. Increasing evidence suggests that NOX and mitochondrial-generated ROS play a crucial role in the optimal activation of lymphocytes and monocytes, which are essential for an effective response to infectious agents (Pearce and Pearce, 2013). Mitochondrial ROS production is important for the activation of multiple Toll-like receptors (TLRs) and the RIG-I-like receptors (RLRs) (West et al., 2011) as well as in the activation of inflammasomes (Tschopp and Schroder, 2010) and the activation and proliferation of T cells (Sena et al., 2013). The inflammasome induces proteolytic processing of proinflammatory cytokines by recognizing various PAMPs) and DAMPs. Hence, it is reasonable to suggest that the perturbation of this intricate mechanism of ROS by exogenous agents possessing antioxidant properties may not yield a noticeable amelioration in the overall prognosis of the organ implicated in the context of multiple organ failure. The physiological responses of inflammatory cells are influenced by various levels of ROS. Elevated intracellular ROS concentrations are closely linked to the manifestation of increased inflammatory responses, specifically those characterized by cytokine storm ( Figure 4 ). Conversely, diminished ROS levels have been correlated with a hypoactive inflammatory response, which can subsequently result in immunosuppression. The presence of ROS within the intermediate range has been observed to exhibit a correlation with immune cell function within the normal range ( Figure 2 ). Hence, the effectiveness of antioxidants is contingent upon the generation of ROS within inflammatory cells. The utilization of antioxidants has been postulated to yield advantageous outcomes in instances characterized by increased inflammatory reactions ( Figure 2 ), yet it may prove to be deleterious in circumstances marked by a relative state of immunosuppression. Hence, the effectiveness of antioxidants is contingent upon an individual’s inflammatory response profile, wherein the precise timing and duration of antioxidant administration play a crucial role in manifesting a beneficial outcome (Jain and Chandel, 2013).

IL-7, a cytokine, exhibits a plethora of supplementary actions that manifest considerable advantageous effects in sepsis, and it has the capacity to counteract a significant pathological aberration observed in sepsis. For example, the administration of IL-7 has been observed to inhibit the process of lymphocyte apoptotic cell death that is induced by sepsis. This effect is achieved through the upregulation of the anti-apoptotic molecule Bcl-2 (Unsinger et al., 2010; Venet et al., 2012). Furthermore, IL-7 enhances the proliferation of lymphocytes by exerting its influence on the activation of the PI3 kinase pathway (Venet et al., 2012). The intervention of IL-7 holds promise for the restoration of functional capabilities in T cells that are characterized by hyporesponsiveness or exhaustion, a common feature observed in sepsis (Kasten et al., 2010; Unsinger et al., 2010, 2012; Venet et al., 2012). IL-7 facilitates communication between Th1 and Th17 lymphocytes in sepsis, resulting in enhanced neutrophil recruitment and bacterial clearance without increasing early tissue injury (Kasten et al., 2010). The administration of IL-7 exhibited a beneficial effect on the decline of immune effector cells, thereby enhancing various lymphocyte functions such as activation, proliferation, expression of adhesion molecules, and production of interferon-γ. The observed advantageous impacts of IL-7 were found to be correlated with an augmentation in overall immune function, as evidenced by an intensified delayed-type hypersensitivity reaction and a notable enhancement in survival rates (Unsinger et al., 2012). Furthermore, the findings of a preclinical study examining the efficacy of recombinant human IL-7 (rhIL-7) as a lymphostimulating intervention in sepsis revealed that the ex vivo administration of rhIL-7 to patients’ cells resulted in a noteworthy enhancement of lymphocyte functionality in various aspects, including the proliferation of CD4(+) and CD8(+) lymphocytes, the production of IFN-γ, the phosphorylation of STAT5, and the induction of B cell lymphoma 2 following stimulation (Venet et al., 2012). Furthermore, it has been observed that this increase in expression also leads to a greater diversity in T-cell receptors. Consequently, this enhanced diversity contributes to a more robust and potent immune response against various pathogens (Lévy et al., 2012; Morre and Beq, 2012). The reversal of T-cell dysfunction and subsequent pathogen clearance can be achieved through the utilization of antibody blockade targeting PD-1 or its ligand, PD-L1. The inhibition of the PD-1 pathway results in enhanced survival outcomes in animal models of bacterial and fungal sepsis that closely resemble the clinical context (Brahmamdam et al., 2010; Zhang et al., 2010).

IL-15, a versatile cytokine, exhibits a close relationship with IL-7 (Inoue et al., 2010). It exerts its effects on both CD4 and CD8 T cells, stimulating their proliferation while concurrently inhibiting apoptosis. One potential advantage of IL-15 in comparison to IL-7 lies in its robust immunostimulatory and proliferative properties, particularly regarding natural killer cells and dendritic cells. The cellular entities play crucial roles in the immune response against pathogenic invasion while concurrently experiencing significant depletion during pathological conditions like sepsis. The administration of IL-15 exhibited a significant inhibitory effect on sepsis-induced apoptosis of CD8 T cells, natural killer cells, and dendritic cells. Furthermore, this intervention demonstrated a notable enhancement in survival rates among subjects afflicted with sepsis resulting from CLP, as well as P. aeruginosa pneumonia (Inoue et al., 2010). Similarly, the administration of interferon γ (IFN-γ) exhibited a notable reversal of the monocyte dysfunction induced by sepsis, leading to a successful resolution of the septic insult (Nalos et al., 2012). The IFN-γ therapy in persistent staphylococcal sepsis elicited a notable upregulation of human leukocyte antigen complex (HLA-DR) expression on monocytes, accompanied by a discernible augmentation in the population of CD4 T cells producing IL-17. Furthermore, this therapeutic intervention demonstrated a favorable clinical outcome, leading to the resolution of sepsis (Nalos et al., 2012).

The efficacy of an immunostimulatory therapeutic strategy hinges upon the implementation of personalized, precise, and temporally optimized interventions. It is imperative to note that the aforementioned approach exclusively confers advantages to septic patients who exhibit immunosuppressive tendencies. The expeditious identification of sepsis-induced epigenetic alterations in specific patients afflicted with sepsis has the potential to facilitate prompt recognition of an immunosuppressive condition, thereby enabling the administration of immune-enhancing therapy in a more timely manner.

In summary, while the primary therapeutic approach for sepsis typically revolves around fluid therapy and antimicrobial agents, it is worth considering the potential role of antioxidants as an adjunct in the management of this medical condition. While antioxidants with simultaneous antimicrobial capabilities may appear promising as an adjunct therapy for sepsis, it is important to carefully evaluate the pros and cons of using antioxidants in the therapeutic approach to sepsis. In addition, the precise timing and the specific clinical circumstances of the individual must be taken into careful consideration when determining the appropriate administration of antioxidants. Antioxidant multitherapy is recommended alongside the primary treatment for sepsis, considering the lack of substantial benefit observed in clinical trials involving antioxidant monotherapy. The administration of a variety of antioxidant agents presents a favorable approach in therapeutic interventions, as it allows for the utilization of treatments that are enhanced by the additive or synergistic interactions across multiple pathways, thereby augmenting the overall antioxidant defense mechanisms (Marshall, 2014). Immunoadjuvant therapy using IL-7 and IL-15, administration of interferon γ, and targeting PD-1, particularly to septic patients who exhibit immunosuppressive tendencies, signifies a significant forthcoming breakthrough in the realm of sepsis. However, in instances characterized by the occurrence of a cytokine storm, wherein an exacerbated inflammatory reaction is observed, such as in the case of ARDS, the administration of antioxidants has been postulated to yield potential benefits in the suppression of the immune response. It is noteworthy to mention that the implementation of research-based recommendations regarding the acute management of sepsis and septic shock is crucial for improving outcomes for critically ill patients with excessive mortality rates (Rhodes et al., 2017). In order to establish reliable recommendations, it is crucial to conduct thorough research, particularly through well-designed randomized controlled trials that explore various aspects of multi-antioxidant therapy or immunoadjuvant therapy.

DS: Conceptualization, Data curation, Formal Analysis, Investigation, Methodology, Resources, Software, Visualization, Writing – original draft, Writing – review & editing. DW: Conceptualization, Funding acquisition, Writing – review & editing. AP: Investigation, Writing – review & editing. BP: Data curation, Writing – review & editing. VY: Investigation, Writing – review & editing. AsP: Conceptualization, Supervision, Writing – review & editing. AJ: Conceptualization, Writing – review & editing.