DOI: https://doi.org/10.61189/398977gdmjky

Received March 10, 2026; Accepted May 12, 2026; Published June 12, 2026

1 CLINICAL CHALLENGES OF SEVERE INFECTIONS

The increasing incidence of severe infections is one of the most formidable challenges for critical care medicine, and it is increasingly common worldwide. The epidemiology shows that millions are admitted annually for sepsis and related morbidities, with age-dependent surges in the incidence of sepsis, and a higher risk among elderly patients or those with comorbid conditions [1]. Severe infections have highly variable clinical follow-up needs. Continuous development of antibiotics and intensive care units, along with early diagnosis and combined targeted treatments, still plays a key role in reducing patient mortality.

Severe infection progresses rapidly and is hard to identify, so early recognition is critical to lowering mortality. Conventional inflammatory markers are slow to respond although they are relatively sensitive to stress. Blood cultures (BC) are sensitive, and BC identification detects 50–80% of mixed infections [2, 3]. However, data from large cohorts indicate that only half of cases are accurately diagnosed, since BC often fails to identify low-virulence organisms [2]. Thus, the simultaneous detection of multi-biomarkers has attracted wide research attention to get a balance between sensitivity and specificity for optimal diagnosis and risk stratification.

This diagnostic challenge is particularly evident in vulnerable populations, such as neonates and preterm infants, in whom severe infections may progress rapidly and lead to high mortality in the neonatal intensive care unit. From a clinical perspective, early diagnosis is crucial with the requirement of simultaneous identification of platelet count and platelet indices to optimize comorbid status [4]. Combined detection of multiple biomarkers is an important means to promote early identification of infection; however, clinical application issues remain unsolved, such as lack of standardization, and the approach is risk-dependent.

2 TYPES AND FUNCTIONS OF BIOMARKERS

2.1 Classification of common biomarkers

Biomarkers of severe infection may be classified based on their origin and functions. Systemic inflammatory response is characterized by so-called pro-inflammatory cytokines, such as C-reactive protein (CRP), procalcitonin (PCT), and interleukin (IL)-6. IL-2 and IL-6 also contribute to improved diagnosis of bacterial infection in laboratory testing. Immune-related biomarkers, such as IL-10 and tumor necrosis factor-α (TNF-α), reflect host immune shifts in sepsis; elevated IL-10 indicates immunosuppression and poor prognosis, whereas increased TNF-α suggests hyperinflammation and worse outcomes [5, 6]. Infection-related organ injury is assessed with lactate and liver/kidney function tests. All of these biomarkers can be affected by confounding factors, so the diagnostic and prognostic effects are complementary, warranting their combined use in clinical practice.

2.2 Roles of various biomarkers in diagnosis

Various infection biomarkers serve distinct diagnostic roles. Pathogen-related markers (such as PCT) identify bacterial infections and assess severity; inflammatory or immune-related markers indicate inflammatory and immune status; organ function-related markers evaluate disease progression and prognosis. Combining markers may enhance sensitivity and support early diagnosis. However, biomarker results should be interpreted alongside clinical conditions and individual characteristics to avoid overreliance on a single marker and ensure accurate diagnosis and treatment.

2.3 Research progress on emerging biomarkers

Emerging multi-omics technologies have revealed new biomarkers for severe infections, including immune checkpoint molecules, extracellular vesicle miRNAs, metabolomics, and host transcriptomics. One candidate marker is histone H3 lysine 18 lactylation, which reflects disease severity and regulates macrophage anti-inflammatory function during sepsis through arginase-1 expression and inflammatory factors [7]. For example, extracellular vesicle-derived miRNA signatures have shown high diagnostic accuracy for septic shock, with a three-miRNA model (miR-100-5p, miR-148a-3p, and miR-451a) achieving an area under the curve of 0.894 in validation cohorts [8]. These functional biomarkers reveal immune dysregulation characterized by concurrent inflammation enhancement and immune evasion, paving the way for early risk stratification, prognostic assessment, and personalized therapy. However, there is a lack of standardization, accompanied by high cost and limited accessibility.

3 ADVANTAGES OF COMBINED DETECTION

3.1 Improved sensitivity and specificity

Systemic combined detection of severe infection markers improves diagnostic sensitivity and specificity. Individually, single biomarkers fail to detect early infections due to biological variation and comorbidities. However, multi-biomarker evaluation offsets these limitations through complementary effects. For example, combined detection of IL-6 and PCT showed a sensitivity of 93.84% and a specificity of 96.72% for severe bacterial infection [9]. Thus, combined detection supports early diagnosis and individualized clinical decision-making.

3.2 Promoting the practice of individualized medicine

Multiplex detection of severe infection biomarkers reflects the inflammatory and immune status to guide individualized medicine. IL-1β, IL-6, and TNF-α are significantly elevated in sepsis-induced cardiomyopathy, and their combined detection improves diagnostic and prognostic evaluation [10]. These inflammatory factors and related parameters could be incorporated to dynamically assess infection severity and progression, thereby guiding antimicrobial therapy, identifying high-risk patients, and tailoring interventions, serving as a quantitative prognostic reference.

3.3 Improving clinical decision-making and patient prognosis

Multiplex detection improves the early diagnosis of deep infections, aiding risk stratification and therapy. Tracking IL-6, PCT, and CRP identifies high-risk patients for timely treatment and monitoring adjustments. No single biomarker is diagnostic by itself and must align with clinical data. Simultaneous detection enhances diagnostic accuracy and enables individualized management of severe infections, as shown in Figure 1.

4 RISKS OF OVER-RELIANCE ON COMBINED DETECTION

4.1 Potential risks of misdiagnosis and missed diagnosis

These biomarkers indicate immune dysregulation involving both inflammatory amplification and suppression, supporting early stratification, prognostic assessment, and individualized therapy. However, lack of standardization, high cost, limited availability and insufficient validation restrict clinical use. Pro- and anti-inflammatory cytokines in hypothermic sepsis are generally low, and combined detection may fail to detect these cytokines, increasing false negatives [11]. Ignoring history, signs and imaging leads to misdiagnosis and mistreatment. Thus, combination assays must be applied within the clinical context and interpreted cautiously.

4.2 Increased healthcare costs and resource waste

Multiplex biomarker detection may improve the diagnostic sensitivity for severe infections, but at a high cost. Repeated testing increases expenses, prolongs hospitalization and treatment, and consumes resources. Without specific indications, no evidence shows combined detection improves outcomes; instead, it burdens laboratories and adds cost. Hence, evaluating the economic value and clinical necessity of multiplex biomarker testing is necessary for rational and sustainable clinical management.

4.3 Risk of deviating from clinical judgment

Simultaneous evaluation of PCT, CRP, and IL-6 may improve diagnostic and prognostic assessment in severe infection and support clinical decision-making before pathogen identification [12]. As shown in Figure 2, IL-6 increases earlier than PCT, a bacterial infection marker. PCT and lactate require serial monitoring with the Sequential Organ Failure Assessment score to predict shock risk. However, biomarker levels vary with age and comorbidities, and overreliance may obscure accurate assessment and cause overtreatment. Thus, biomarker detection should be integrated with symptoms, signs, and imaging to guide individualized management.

5 FUTURE DIRECTIONS AND PRACTICAL RECOMMENDATIONS

Advances in molecular diagnostics and high-throughput technologies enable precise multidimensional detection of severe infection biomarkers. Liquid biopsy, single-cell analysis, and multiplex immunoassays jointly assess multiple biomarkers, improving sensitivity and specificity. Artificial intelligence and machine learning (e.g., Light Gradient Boosting Machine, Extreme Gradient Boosting Machine, Random Forest) show strong predictive ability in sepsis-associated liver injury. Stacked ensembles enhance prediction robustness for early intervention and personalized therapy [13]. These research findings indicate that the future application of biomarkers should not be limited to the interpretation of a single biomarker, but rather should combine molecular indicators with clinical variables. Nonetheless, these emerging techniques are in need of multi-center validation and guideline development for clinical application in order to tackle issues concerning standardization, cost, and practicability.

Clinically, it is often difficult to distinguish infection-related complications solely based on traditional biomarkers. Therefore, comprehensive analysis is particularly important. Pneumonia, severe sepsis and septic shock are common complications in patients following an out-of-hospital cardiac arrest and are associated with high mortality. PCT and CRP provide limited diagnostic value for infectious complications, and hence lead to incorrect diagnoses derived from electronic medical records if used as the sole biomarkers [14]. Integrating clinical data with biomarker results leads to improved diagnoses and therapy. Biomarkers should be interpreted dynamically against the background of disease progression, comorbidities, infection risk, imaging, microbiology and vital signs to enable comprehensive decision-making. Unifying interpretations may help standardize use, reduce unnecessary interventions and facilitate early identification and targeted treatment of severe infections.

In addition to diagnosis and risk prediction, biomarker-guided strategies also have practical value in treatment monitoring and antimicrobial stewardship. Evidence-based protocols for combined biomarker assessment in severe infections should define each biomarker’s role in diagnosis, monitoring, and treatment evaluation. A PCT-based algorithm guiding antibiotic use in acute pancreatitis reduced unnecessary antimicrobial exposure without compromising safety [15]. Age, comorbidities, and immune status must be considered when setting thresholds and strategies. Overall, future efforts should not only expand biomarker detection but also establish a clinically validated, cost-effective, and dynamically interpretable detection strategy. Through multi-center research, standardized biomarker combinations, thresholds for different disease stages, and clinical decision-making algorithms should be developed. In particular, the detection results of biomarkers should be combined with patients’ clinical signs, imaging, microbiology, and electronic health data. Eventually, the combined detection of biomarkers can not only be used for the early diagnosis of infectious diseases, but also for risk stratification, treatment monitoring, and antibiotic management of severe infections.

DOI: https://doi.org/10.61189/037416axzkek

Received April 16, 2026; Accepted June 1, 2026; Published June 12, 2026

DOI: https://doi.org/10.61189/114823yjtjfu

Received December 21, 2025; Accepted April 20, 2026; Published June 15, 2026

1 INTRODUCTION

Perioperative blood pressure (BP) control is a cornerstone of anesthesiology, as it significantly affects organ recovery and the development of postoperative complications. In pediatric patients undergoing cardiopulmonary bypass, brain injury is associated with impaired cerebral autoregulation. Accurate adjustment of mean arterial pressure (MAP) can preserve cerebral perfusion and thus minimize neurological injury [1]. Hypotension often leads to insufficient perfusion of the brain, heart, and kidneys, resulting in complications such as acute kidney injury (AKI) and cerebral ischemia. 

Recent advancements have shifted perioperative BP management from empirical to goal-directed approaches. For instance, transcranial Doppler monitors cerebral blood flow following vascular occlusion to prevent hyperperfusion. Tools such as esophageal Doppler and the pressure recording analytical method (PRAM) enable more precise titration of circulatory dynamics. Low-dose continuous norepinephrine (NE) infusion combined with goal-directed fluid therapy has been shown to reduce complications in elective pulmonary surgery [2]. The prophylactic use of vasoactive agents and the renal-protective effects of dexmedetomidine (DEX) provide additional strategies for effective perioperative BP control. Defining personalized safety thresholds and integrating multimodal monitoring remain critical challenges. Notably, lower MAP is strongly associated with postoperative AKI, while post-induction hypotension independently increases the odds of adverse events in transcatheter aortic valve replacement [3].

2 MECHANISMS AND IMPACT OF PERIOPERATIVE BP MANAGEMENT

2.1 Effects of BP fluctuations on organ perfusion

Hemodynamic changes during the perioperative period can exert a significant impact on organ perfusion and function. In patients with aneurysmal subarachnoid hemorrhage, the oxygen reactivity index shows superior sensitivity in detecting perfusion derangements associated with delayed cerebral ischemia [4]. While compensatory microcirculatory mechanisms may preserve certain mucosal functions during hypotension, accurate BP control remains vital for critical organs. Personalized BP control based on dynamic hemodynamic variations may attenuate the risk of perfusion mismatch that leads to organ injury. Current clinical consensus suggests that maintaining MAP within 10% of the patient' s baseline or keeping the cerebral oxygenation index below 0.3 serves as a critical threshold for organ protection.

2.2 Correlation between hypotension and postoperative cerebral complications

Perioperative hypotension contributes to cerebral complications through reduced perfusion pressure and disruption of the blood–brain barrier. Orthostatic hypotension is associated with cognitive impairment and microstructural brain damage. However, personalized protocols that maintain cerebral oxygenation within optimal ranges show promise for reducing neurological complications. In addition, acute water intake has been shown to improve orthostatic tolerance in patients with orthostatic hypotension and reduce performance decline associated with insufficient cerebral perfusion, offering a simple perioperative neuroprotective strategy [5]. A critical threshold is typically defined as an absolute MAP below 65 mmHg or a decrease of more than 20% from the pre-induction baseline, both of which significantly elevate the risk of cognitive impairment.

2.3 BP-related mechanisms of cardiac and renal dysfunction

Perioperative BP variability profoundly impacts hemodynamic stability and organ perfusion, thereby influencing both cardiac and renal function. Intraoperative hypotension—especially a decrease in MAP—can lead to insufficient myocardial perfusion and ischemic damage; therefore, stable BP is essential for cardiac protection. Higher blood pressure variability (BPV) during cardiopulmonary bypass—particularly when MAP fluctuations exceed 30% of the area under the curve—is significantly associated with cardiac surgery-associated AKI in pediatric patients [6]. For adults, a cumulative duration of MAP below 60 mmHg for more than 20 minutes is identified as a critical threshold for stage 1 AKI.

Perioperative hemodynamic instability—characterized by chronic or repeated episodes of hypotension, hypertension, or increased BPV—leads to microcirculatory deterioration and disruption of autoregulatory responses, ultimately resulting in target organ injury (Figure 1). Notably, patients with chronic hypertension are more prone to these variations due to preexisting arteriolosclerosis and impaired renal autoregulation. This cardiorenal interaction illustrates the complex relationship between hemodynamic instability and organ perfusion in a vulnerable state. Such pathophysiological processes highlight the importance of personalized and dynamic BP management to reduce intraoperative shock and improve early postoperative outcomes.

3 INNOVATIVE MANAGEMENT STRATEGIES AND CLINICAL PRACTICE

Individualized BP management guided by real-time monitoring is essential for preventing complications. Esophageal Doppler-guided therapy decreases pulmonary complications and hospital length of stay, while the PRAM facilitates postoperative triage and reduces healthcare costs. Continuous arterial pressure monitoring and AI-based algorithms enable clinicians to dynamically assess circulatory status. Closed-loop control systems further improve hemodynamic stability. Ac-curate pharmacological regulation effectively protects organ function. Prophylactic NE infusion is superior to bolus epinephrine for reducing post-induction hypotension and complications in major abdominal surgery. Continuous DEX infusion for 24 hours significantly lowers the rate of AKI rates by 29% without hemodynamic risks. Titratable, short-acting α-adrenergic agonists permit stable perfusion and minimize organ injury. Furthermore, closed-loop administration of NE significantly decreases the incidence of postoperative hypotension in ICU patients following cardiac surgery [7].

The integration of continuous BP monitoring with advanced AI algorithms facilitates real-time recognition of hemodynamic changes. Notably, the ClearSight system provides safe, non-invasive arterial pressure measurement via a finger cuff, offering a viable alternative for neurovascular surgery. In the future, these intelligent technologies could be incorporated into a "prediction–prevention–intervention" model to provide more precise control and further reduce perioperative complications [8]. A variety of commonly used perioperative antihypertensive drugs with differentiated administration regimens and corresponding clinical trial outcomes are summarized in Supplementary Table 1.

4 DISCUSSION

4.1 Multidisciplinary collaboration in perioperative BP management

Optimization of perioperative BP is an important factor in preventing postoperative organ dysfunction, and collaboration among various disciplines (anesthesiology, surgery, critical care, and nursing) is crucial for its successful implementation. Real-time monitoring-guided, patient-specific BP management strategies may facilitate optimal intraoperative and postoperative decision-making. For instance, intraoperative transcranial Doppler monitoring allows early detection of cerebral hyperperfusion syndrome after carotid endarterectomy, whereas esophageal Doppler and PRAM improve the reliability of hemodynamic data and contribute to continuity of care [9]. With multidisciplinary support, encephaloduroarteriosynangiosis can be optimally performed with further improvements in surgical techniques, strict hemodynamic control during anesthesia, and versatile methods of medical management [10]. In the future, establishing standardized collaborative workflows, improving information exchange, and enhancing team training will be crucial for transitioning BP intervention from isolated treatment to coordinated, whole-process management.

4.2 Key challenges and emerging research priorities

Despite exciting advances in personalized BP management for preventing postoperative organ injury, major hurdles remain in implementing this approach at the bedside. The use of real-time monitoring systems is restricted by their availability and the lack of standardized operating procedures, which hinders their application in primary hospitals. BPV can influence cerebral perfusion and is associated with the development of ICU delirium; however, its mechanistic involvement in organ injury, diagnostic parameters, and therapeutic targets have yet to be elucidated [11]. Combined pharmacological and technological approaches, such as closed-loop NE infusion systems, appear promising for improving BP control; however, there is a lack of evidence regarding their long-term beneficial impact and cost-effectiveness. Furthermore, the ClearSight system enables non-invasive arterial pressure measurement via a finger cuff and may be a safe alternative for use in neurovascular surgery [8]. Future research should focus on intelligent, non-invasive monitoring technologies, multicenter randomized controlled trials, and integrated models that combine biomarkers with hemodynamic parameters to enable precise risk stratification and targeted interventions.

4.3 The role of BP management in overall postoperative recovery

Precise perioperative BP management can markedly lower the incidence of complications in vital organs such as the brain, heart, and kidneys and improve microcirculation and postoperative lung function. These factors contribute to reduced hospital length of stay and improved long-term outcomes. In cardiac surgery, intraoperative DEX can preserve renal function and reduce the use of vasopressors [12]. Goal-directed hemodynamic therapy makes pulmonary recovery more efficient and improves overall rehabilitation. Additionally, combined aerobic and resistance training has been shown to be more effective than aerobic training alone in reducing BP and its variability [13]. Integrating BP management into a comprehensive "surgery–monitoring–rehabilitation" pathway, together with early mobilization and nutritional support, enables the establishment of a patient-centered, multidimensional rehabilitation system that substantially improves the overall quality of perioperative care.

5 CONCLUSION AND CLINICAL IMPLICATIONS

Accurate perioperative BP control is essential for avoiding postoperative multiorgan failure. Although current evidence highlights the critical importance of personalized management, several clinical gaps remain. One major limitation is the lack of universal, high-level evidence that specifically defines "critical thresholds" across diverse surgical populations. Most current studies rely on retrospective data, which may not fully account for individual patient baseline variability [14].

Future research should prioritize multicenter randomized controlled trials to validate the long-term cost-effectiveness and clinical outcomes of intelligent closed-loop infusion systems. Furthermore, integrating non-invasive monitoring technologies with machine-learning algorithms will be crucial for transitioning from reactive treatment to proactive, predictive interventions.

Finally, the successful implementation of these strategies requires robust multidisciplinary collaboration and standardized educational protocols. The ultimate goal is to establish a patient-centered, multidimensional "prediction–prevention–rehabilitation" pathway that ensures safer perioperative recovery, even in resource-limited settings.

Yalin Zhu^1,2,*, Long Peng^2,*, Yimin Zhang¹, Haiwen Wang¹, Wen Xu<sup>1

1</sup>Department of Anesthesiology, Naval Hospital of Eastern Theater, Zhoushan 316004, Zhejiang, China.
²Department of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai 200433, China.
^*The authors contribute equally.

Address correspondence to: Wen Xu, Department of Anesthesiology, Naval Hospital of Eastern Theater, No. 98 Wenhua Road, Dinghai District, Zhoushan 316004, Zhejiang, China. E-mail: xuwennhet@163.com.

DOI: https://doi.org/10.61189/379279kecswz

Received September 25, 2025; Accepted May 20, 2026; Published June 17, 2026

Oxidative stress serves as the central pathological hub of various major diseases such as cancer, neurodegenerative disorders, sepsis, and perioperative organ injury. Its core is an imbalance between reactive oxygen species (ROS) production and the body' s antioxidant defense system, which can bidirectionally regulate DNA damage and immune activation. Therefore, understanding its homeostatic mechanisms is critical for disease prevention and treatment, particularly in organ protection and prognosis improvement for perioperative anesthetized and critically ill patients (Figure 1).

1 THE IMBALANCED ESSENCE OF OXIDATIVE STRESS

The core of oxidative stress is the functional mismatch between ROS generation including superoxide anion, hydrogen peroxide and other species, and the activity of antioxidant systems including superoxide dismutase, glutathione and catalase, rather than an absolute increase in ROS levels. Its biological effects are highly dependent on concentration, duration of action and cellular compensatory capacity [1].

Moderate, controlled oxidative stress can function as a physiological signaling cue to trigger immune responses and facilitate pathogen clearance; conversely, excessive, sustained oxidative stress induces irreversible damage to biological macromolecules including lipids, proteins and DNA [1]. Taking the classic oxidative stress inducer H₂O₂ as an example, at low concentrations ranging from nanomolar to low micromolar levels, ROS govern key signaling pathways such as protein kinase B phosphorylation via reversible redox modification; once concentrations exceed the cellular tolerance threshold such as ≥100 μM, ROS shift to a potent cytotoxic agent that triggers cell death and tissue injury [2]. Notably, telomeric DNA at chromosome ends is highly vulnerable to ROS attack. Persistent oxidative stress accelerates telomere shortening and dysfunction, induces cellular senescence and genomic instability, features that are also core mechanisms underlying inflammatory diseases, malignant tumor progression, and accelerated perioperative organ senescence [2]. Clinical scenarios including perioperative ischemia-reperfusion, mechanical ventilation, anesthetic exposure and sepsis are all key triggers of systemic oxidative stress imbalance in the body.

2 DNA DAMAGE EFFECTS MEDIATED BY OXIDATIVE STRESS

Sustained ROS attack on DNA elicits multiple forms of damage, including base oxidation typified by 8-oxoguanine formation, DNA strand breaks, and protein-DNA cross-linking. The body executes damage repair via multi-tiered mechanisms such as base excision repair, nucleotide excision repair and homologous recombination repair. Among these, key base excision repair pathway enzymes such as 8-oxoguanine DNA glycosylase 1 not only directly repair oxidized bases, but also preserve tissue barrier integrity and immune microenvironment homeostasis by regulating cytokine expression [3].

The primary pathogenic consequence of persistent oxidative stress is not mere cytotoxicity, but the accumulation of oncogenic mutations driven by induced genomic instability, coupled with epigenetic alterations including DNA methylation and histone modification. These changes collectively drive uncontrolled cell proliferation and apoptotic evasion, ultimately promoting tumor initiation and progression [1]. Cancer cells consistently maintain higher ROS levels than normal cells: on one hand, they drive proliferative and survival signaling via activation of pathways such as mitogen-activated protein kinase-extracellular signal-regulated kinase and phosphoinositide 3-kinase-protein kinase B; on the other hand, they counteract the cytotoxicity of elevated ROS by upregulating antioxidant transcription factors such as nuclear factor erythroid 2-related factor 2 (Nrf2) and reprogramming metabolic pathways, thereby sustaining malignant progression [4]. In the fields of anesthesiology and critical care medicine, persistent oxidative stress induced by pathological states including perioperative ischemia-reperfusion, cardiopulmonary bypass, and sepsis disrupts DNA damage-repair homeostasis in vital organ cells such as renal tubular epithelial cells, alveolar epithelial cells, and cardiomyocytes. This disruption represents the core pathological mechanism underlying the development of postoperative multiple organ dysfunction syndrome.

3 OXIDATIVE STRESS AND IMMUNE ACTIVATION

Oxidative stress exhibits a tightly regulated threshold effect in modulating immune responses. Physiological levels of ROS are indispensable for normal immune system activation: during the innate immune phase, ROS promote macrophage polarization toward the pro-inflammatory M1 phenotype, stimulate the release of cytokines such as tumor necrosis factor-alpha and interleukin-1 beta, and enhance Toll-like receptor pathway activity and macrophage bactericidal capacity [5]. During antigen presentation, ROS upregulate dendritic cell expression of major histocompatibility complex class II molecules and costimulatory molecules via nuclear factor kappa-B pathway activation, boosting antigen presentation efficiency [6]. During the adaptive immune phase, ROS finely tune T cell activation and differentiation to maintain normal host defense function [7].

However, when oxidative stress remains chronically uncontrolled, physiological immune activation quickly transitions into chronic inflammation and immune dysfunction, acting as a key pathogenic driver of disease progression. This effect is particularly pronounced in the tumor microenvironment: ROS produced by cancer cells and stromal cells induce the infiltration of immunosuppressive cells, establishing a self-reinforcing positive feedback loop between oxidative stress and inflammation that ultimately drives immune escape [8]. In perioperative and critical care settings, this threshold effect directly determines patient prognosis: uncontrolled oxidative stress in patients with sepsis and acute respiratory distress syndrome not only triggers cytokine storms to exacerbate tissue injury, but also induces aberrant macrophage polarization and T cell exhaustion, leading to immune paralysis and significantly increasing the risk of secondary infection and mortality. Meanwhile, anesthetic agents and perioperative management strategies can modulate postoperative immune function and infection risk by regulating systemic oxidative stress levels.

4 PRECISE INTERVENTION STRATEGIES BASED ON REDOX HOMEOSTASIS

The dual nature of oxidative stress dictates that the core of clinical intervention is precision-targeted homeostasis control—excessive oxidative stress can be corrected via antioxidant strategies to mitigate DNA damage for disease prevention and organ protection, while moderate oxidative stress can be strategically harnessed in specific contexts to activate immunity, or tumor cell redox homeostasis can be selectively disrupted to induce cancer cell death.

Nevertheless, traditional non-selective antioxidant therapies carry marked clinical limitations. Multiple large-scale clinical trials and basic studies have confirmed that universal antioxidant supplements yield no preventive or therapeutic benefits, and instead increase lung cancer risk in smokers and accelerate tumor growth in murine models, fully demonstrating that disruption of redox homeostasis on either end exacerbates pathological progression [9, 10]. In anesthesiology and critical care medicine, regulating redox balance has emerged as a research focus for perioperative organ protection and critical care management. Use of volatile anesthetics and clinically routine agents such as dexmedetomidine can moderately modulate ROS levels and activate the Nrf2 antioxidant pathway, attenuating ischemia-reperfusion induced DNA damage and immune dysfunction to confer perioperative protection for vital organs including the heart, brain and kidneys. For sepsis treatment, research has abandoned non-selective antioxidant therapy, shifting focus to precise intervention strategies that target excess ROS clearance while preserving the physiological immune-activating function of ROS.

In addition, strategies targeting the disruption of tumor cell redox homeostasis have demonstrated notable translational potential. For instance, nanocatalytic platforms can specifically amplify oxidative damage in tumor tissues and block DNA repair pathways to achieve precision anti-tumor therapy. The development of detection technologies for highly sensitive oxidative stress biomarkers such as 8-oxo-7, 8-dihydro-2'-deoxyguanosine has also laid critical groundwork for accurate assessment of patient oxidative stress status and implementation of individualized interventions [11].

5 CONCLUSION

In summary, oxidative stress modulates two core biological processes, DNA damage and immune activation, simultaneously via concentration-dependent bidirectional effects. Future research and clinical practice should focus on the precise identification and control of redox balance points in specific pathological microenvironments, minimizing pathological DNA damage while preserving or enhancing physiological immune activation, ultimately delivering optimized strategies for the prevention and treatment of tumors, perioperative organ injury, severe sepsis and other related diseases.

DOI: https://doi.org/10.61189/173560pysjvg

Received December 17, 2025; Accepted April 20, 2026; Published June 18, 2026

DOI: https://doi.org/10.61189/095460hkaaqf

Received January 7, 2026; Accepted March 26, 2026; Published June 18, 2026

College of Integrated Traditional Chinese and Western Medicine, Nanchang Medical College, Nanchang 330052, Jiangxi, China.

Address correspondence to: Chenlei Qian, College of Integrated Traditional Chinese and Western Medicine, Nanchang Medical College, No. 689 Huiren Avenue, Xiaolan Economic Development Zone, Nanchang 330052, Jiangxi, China. E-mail: 2286990788@qq.com.

DOI: https://doi.org/10.61189/693733xrbrvc

Received October 16, 2025; Accepted April 30, 2026; Published June 18, 2026

DOI: https://doi.org/10.61189/650911qrvsug

Received December 21, 2025; Accepted May 8, 2026; Published June 18, 2026

1 INTRODUCTION 

Organ transplantation is widely recognized as the most effective therapy for patients with end-stage organ failure. Over the past decades, advances in surgical techniques and immunosuppressive therapies have significantly improved graft survival and patient outcomes. Nevertheless, the global shortage of donor organs remains a critical challenge in transplantation medicine. The demand for transplantable organs far exceeds the available supply, leading to prolonged waiting lists and increased mortality among patients awaiting transplantation.

To address this challenge, research in transplantation medicine has evolved along two main directions. One strategy focuses on improving organ preservation and graft viability through advanced techniques such as machine perfusion. These approaches enable metabolic support and functional assessment of donor organs prior to transplantation and have been shown to enhance graft utilization and transplant outcomes [1,  2].

Another promising strategy seeks to expand the donor pool through xenotransplantation. With the development of geneediting technologies, particularly clustered regularly interspaced short palindromic repeats-based approaches, genetically modified porcine organs with reduced immunogenicity have now been generated. These advances suggest that xenotransplantation may become a viable strategy to address the global shortage of transplantable organs [3, 4].

In this perspective article, we examine the technological transition from conventional organ preservation methods to xenotransplantation. We highlight the scientific progress achieved in recent years, discuss the major translational barriers that remain, and consider the ethical and regulatory challenges associated with this emerging field.

2 ADVANCES IN ORGAN PRESERVATION TECHNOLOGIES

2.1 Limitations of conventional organ preservation

Static cold storage (SCS) has long been the standard method for preserving donor organs due to its simplicity and wide accessibility. However, SCS does not fully prevent ischemia–reperfusion injury, which remains one of major causes of delayed graft function and early graft failure after transplantation [5].

These limitations become more evident when marginal organs or extended-criteria donors are used. As transplant programs increasingly rely on such donors to expand the organ pool, preservation-related injury has become a critical factor affecting transplant outcomes. Therefore, improving preservation technologies is essential not only for maintaining graft quality but also for safely increasing organ utilization.

2.2 Machine perfusion as a bridge technology

Machine perfusion technologies have significantly transformed the concept of organ preservation. Unlike SCS, perfusion-based preservation provides continuous oxygen and nutrients to the organ, allowing metabolic activity to be sustained and graft viability to be assessed prior to transplantation.

Clinical studies have demonstrated that ex vivo perfusion can increase the utilization of donor hearts and reduce the incidence of severe primary graft dysfunction after transplantation [1]. Similarly, ischemia-free liver transplantation using continuous perfusion has been shown to improve control of ischemia–reperfusion injury and achieve better postoperative graft function compared with conventional preservation methods [2].

These technological advances suggest that machine perfusion not only improves current transplantation practice but also provides a potential platform for future innovations. In particular, perfusion systems may enable targeted therapies, immune modulation, or functional optimization of donor organs prior to implantation.

Importantly, the development of machine perfusion technologies also provides a technical foundation for future xenotransplantation research. Controlled perfusion environments could facilitate graft evaluation and immune conditioning before transplantation, thereby bridging current allotransplantation techniques and emerging xenotransplantation strategies.

3 XENOTRANSPLANTATION AS A FUTURE STRATEGY

3.1 Gene editing and donor modification

Xenotransplantation has long been proposed as a potential solution to the shortage of human donor organs. Among possible donor species, pigs are considered the most suitable candidates due to their physiological compatibility with humans and the feasibility of large-scale breeding.

Historically, however, xenotransplantation faced strong immune barriers posed by carbohydrate antigens expressed on porcine endothelial cells. Recent advances in gene-editing technologies, particularly clustered regularly interspaced short palindromic repeats-based approaches, have made it possible to remove key xenoantigens and introduce human regulatory genes into donor animals. These genetic modifications significantly reduce the immunogenicity of porcine organs and improve graft survival in experimental models [6].

Preclinical studies using multi-gene-edited pigs have demonstrated prolonged graft survival and improved compatibility between donor organs and recipients [4, 6]. These findings suggest that xenotransplantation may become an important strategy for expanding the donor pool in the future.

3.2 Immunological barriers

Despite these advances, immune rejection remains the central challenge in xenotransplantation. Xenograft rejection can occur at several stages, including hyperacute rejection, acute vascular rejection, and chronic graft injury.

Hyperacute rejection occurs within minutes to hours after transplantation and is primarily mediated by pre-existing natural antibodies that recognize carbohydrate antigens on porcine endothelial cells. This interaction triggers complement activation, endothelial injury, and rapid graft failure [7].

Acute rejection develops over days or weeks and involves both humoral and cellular immune responses. Antibody-mediated injury leads to complement deposition and vascular damage, while immune cells—including macrophages, natural killer cells, and T lymphocytes—contribute to inflammatory graft injury [8, 9].

A schematic overview of these immune mechanisms and the gene-editing strategies used to mitigate them is presented in Figure 1.

4 TRANSLATIONAL MODELS AND CLINICAL PERSPECTIVES

Animal models are essential for bridging experimental research and clinical application in xenotransplantation. Pig-to-nonhuman primate transplantation models are widely used to investigate graft survival, immune responses, and systemic complications associated with xenografts.

Recent studies using genetically modified pigs have demonstrated significant improvements in xenograft survival in preclinical models [6, 8]. These experiments indicate that combining genetic engineering of donor animals with optimized immunosuppressive strategies can substantially reduce early immune injury.

Although these findings are encouraging, additional studies are required to evaluate long-term graft function, immune compatibility, and safety before xenotransplantation can be widely applied in clinical practice.

The major technological advances discussed in this article are summarized in Supplementary Table 1.

5 ETHICAL AND BIOSAFETY CONSIDERATIONS

The development of xenotransplantation raises several important ethical and biosafety questions. One major concern is the welfare of donor animals. The production of genetically modified pigs involves breeding, genetic manipulation, and controlled housing conditions, all of which must follow strict ethical guidelines to ensure humane treatment.

Another important issue is the potential risk of zoonotic infection. Porcine endogenous retroviruses and other porcine microorganisms may theoretically be transmitted to human recipients. Although gene-editing technologies and pathogen-free breeding programs have significantly reduced these risks, long-term monitoring of recipients remains essential [10].

Furthermore, the future implementation of xenotransplantation will depend on public acceptance and transparent regulatory frameworks. Policies addressing donor animal welfare, recipient monitoring, and equitable access to transplantation technologies will be critical for the responsible development of this field.

6 CONCLUSION

Organ transplantation is entering a new era in which advances in organ preservation and the search for alternative donor sources are becoming increasingly interconnected. Machine perfusion technologies have already improved the preservation and evaluation of donor organs, while xenotransplantation offers a potential long-term solution to the global shortage of transplantable organs.

Nevertheless, several scientific and ethical challenges remain. Immune incompatibility, coagulation disturbances, zoonotic infection risks, and regulatory considerations must all be addressed before xenotransplantation can become a routine clinical therapy.

Future progress will require close collaboration across multiple disciplines, including transplantation surgery, immunology, genetic engineering, and bioethics. Through continued technological innovation and responsible governance, xenotransplantation may ultimately provide a sustainable solution for patients suffering from end-stage organ failure.