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REVIEW ARTICLE

Disrupted Cortico-Metabolic Adaptation is Sepsis: Pathophysiologic Basis of Critical Illness Hypoglycemia and Mortality
Ketevan Ghambashidze1,ID, Natalia Pavliashvili1, Data Kekutia2
Received: 20 Nov 2025; Accepted: 3 Dec 2025; Available online: 4 Dec 2025
References
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ABSTRACT
Sepsis is a significant disruptor of endocrine and metabolic homeostasis. During the early adaptive response, the hypothalamic–pituitary–adrenal (HPA) axis is activated to increase glucocorticoid production, promote stress hyperglycemia, and maintain cardiovascular homeostasis. When sepsis persists or is severe, this cortico–metabolic adaptation can fail. Experimental murine models show a transition from an early state of hypermetabolism and hyperglycemia to a hypometabolic state that includes hypoglycemia, lactic acidosis, and organ dysfunction. In critically ill patients, hypoglycemia often indicates failure of hepatic gluconeogenesis, depletion of energy reserves, and low glucocorticoid activity from critical illness–related corticosteroid insufficiency and tissue glucocorticoid resistance. Along with these changes, sepsis also causes metabolic disturbances, including mitochondrial dysfunction characterized by impaired oxidative phosphorylation, increased reliance on anaerobic glycolysis, and tissue accumulation of lactate. These metabolic disturbances create a bioenergetic crisis that can contribute to shock and death. This narrative review compiles findings from sepsis research published between 2020 and 2025 on adrenal axis failure, changes in glucocorticoid receptors, mitochondrial failure, and glucose dysregulation. We present an integrative pathophysiology that explicitly links endocrine and metabolic derangements and hypoglycemia in critical illness, and discuss how the experimental data presented may inform potential adjunctive therapies to restore cortico–metabolic homeostasis in patients with septic shock.
Keywords:  Corticosteroid insufficiency; glucocorticoid resistance; hypoglycemia; mitochondrial dysfunction; sepsis.

DOI: 10.52340/GBMN.2025.01.01.139
INTRODUCTION

Sepsis is characterized as life-threatening organ dysfunction resulting from a dysregulated host response to infection.1 While inflammatory and hemodynamic dysfunctions have historically been the primary focus of research in sepsis, the role of endocrine and metabolic adaptive responses plays a central role in survival as well. In health, stress-response hormones mobilize substrates, limit excessive inflammation, and preserve perfusion. A common feature of early sepsis is hyperglycemia, an increase in blood glucose, driven by catecholamines, glucagon, inflammatory cytokines, and glucocorticoids acting on the liver and muscle.2,3 Even though this is detrimental when extreme, the hyperglycemic state is initially an important adaptive response: it provides sufficient substrate for the immune system and vital organs, as well as supports higher energy demands.3

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Failure to mount or sustain this adaptive response is associated with poorer outcomes. Clinical studies reveal that spontaneous hypoglycemia in septic patients, particularly at presentation or early in the course of their stay in the intensive care unit, significantly increases mortality risk.4 Experimental work in mice confirms similar observations, namely, polygermic sepsis, or endotoxemia, invariably transitions from temporary hyperglycemia to late hypoglycemia, concurrent with hemodynamic collapse and death.5,6 Taken together, these observations show the concept of cortico–metabolic failure, when the adrenal stress response and peripheral metabolic machinery no longer maintain sufficient energy homeostatic function.1,7-9

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This review focuses on information and experimental data obtained from laboratory mouse models published over the last five years. It synthesizes recent experimental findings in support of the hypothesis that a cortico–metabolic failure is the primary mechanism linking endocrine disruption, mitochondrial dysfunction, and the development of hypoglycemia in critical illness.

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We outline the normal HPA response to sepsis and mechanisms leading to adrenal insufficiency and glucocorticoid resistance, describe how inflammatory and endocrine signals reshape glucose metabolism, culminating in hypoglycemia and lactate accumulation and point to a paradigm shift: mortality from sepsis is due not just to uncontrolled inflammation and collapse of circulation forward comorbidities, but progressive disruption of the stress-endocrine system and bioenergetic systems that maintain glucose and ATP homeostasis.1-3,10

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Finally, we examine mitochondrial dysfunction as a unifying mechanism of energy failure and briefly consider translational implications for adjunctive therapies.

REVIEW

HPA axis activation, adrenal insufficiency, and glucocorticoid resistance

Upon acute infection, the HPA axis is rapidly activated. Cytokines such as IL-1β, IL-6, and TNF-α induce the hypothalamus to release corticotropin-releasing hormone. The pituitary gland secretes ACTH, which increases cortisol (in humans) or corticosterone (in mice).11 In the early phase of sepsis, endogenous glucocorticoids are required for survival: they limit excessive inflammation, maintain the function of endothelial and vascular smooth-muscle cells, and promote gluconeogenesis in the liver. Use of adrenalectomy or pharmacologic blockade in murine models consistently shows an increased vulnerability to septic shock, which can be remedied with physiological glucocorticoid replacement.12

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As sepsis progresses into severe or chronic illness, the HPA axis becomes dysregulated. Clinical illness-related corticosteroid insufficiency (CIRCI) denotes a state of reduced glucocorticoids due to the severity of the disease. The causes of CIRCI include: direct injury to the adrenal gland, inadequate ACTH secretion, altered metabolism of circulating cortisol, and—in our view—the more consequential issue of chronic tissue resistance to glucocorticoids.1,13 Up to 50% of patients with septic shock exhibit objective biochemical or functional evidence of HPA axis dysfunction, mirroring other studies in rodent models, in which AcfA-beta corticosterone responses begin to fail despite ongoing maximal inflammatory stress.1,14

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Glucocorticoid resistance is the cellular aspect of CIRCI. In sepsis, inflammatory cytokines and oxidative stress alter the expression and function of the glucocorticoid receptor (GR).7,11,14 Experimental models demonstrate that immune and parenchymal cells downregulate the expression of the active GR-α isoform, alter GR splice variants, become less able to bind ligands (glucocorticoids), and exhibit impaired nuclear translocation.7,8 Reactive oxygen and nitrogen species can also oxidize GR and decrease the affinity for the hormone and target DNA. Concurrently, GR is connected to gluconeogenic and anti-inflammatory gene programs by transcription cofactors such as PGC-1α and p300, but these cofactors are downregulated or sequestered into pro-inflammatory complexes.7 As a result, there may be increased levels of circulating glucocorticoids, but their capacity to alter inflammation and metabolism is blunted.

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Studies in murine models of sepsis have established a link between GR dysfunction and common clinical phenotypes. Mice with impaired GR signaling demonstrate increased vascular leak, hypotension, and hyperlactatemia, even when supratherapeutic levels of corticosterone are present.7,14 Further, reversing GR dysfunction or circumventing GR and acting through downstream effectors has been associated with increased survival in murine models. Antioxidant therapy, particularly high-dose vitamin C, can restore GR ligand- and DNA-binding properties in oxidative conditions, thereby enhancing the efficacy of both endogenous and exogenous glucocorticoids.11 Experimental delivery of GR-induced proteins, such as glucocorticoid-induced leucine zipper (GILZ), also protects against endotoxemic shock, underscoring that adequate glucocorticoid signaling is a prerequisite for maintaining cortico–metabolic stability during sepsis.7

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Glucose metabolism in sepsis: from stress hyperglycemia to hypoglycemia

The metabolic reaction to sepsis occurs in two phases. Initially, catecholamines, glucagon, cortisol, and pro-inflammatory cytokines act to stimulate hepatic glycogenolysis and gluconeogenesis while promoting peripheral insulin resistance.3,15 Glucose and free-fatty-acid levels increase in the circulation, and muscle proteolysis provides amino-acid substrates for hepatic glucose production. The shift into a catabolic, hyperglycemic state is metabolically costly but initially beneficial, ensuring adequate fuel availability to meet the heightened energy demands imposed by fever, tachycardia, and activated immune responses.

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If sepsis extends beyond this, and adequate support is not provided, this adaptive metabolic state will cease. In mouse models of polymicrobial peritonitis or endotoxemia, circulating glucose levels frequently fall precipitously after an initial rise.5,6,9 Furthermore, terminal hypoglycemia is consistently observed in non-survivors. Multiple mechanisms synergistically create this state. First, glycogen stores in the liver are rapidly depleted under the conditions of prolonged stress and diminished nutrient intake.3,5 Second, decreased appetite and enteral intake eliminate exogenous dietary carbohydrate sources and eventually lead to a dependency on gluconeogenesis.3 Third, inflammatory mediators can directly suppress the expression of gluconeogenic enzymes, especially phosphoenolpyruvate carboxykinase and glucose-6-phosphatase.7,16 This mechanism may be further suppressed by loss of GR–PGC-1α signaling and oxidative stress, which further down-regulates gluconeogenic genes.7,8

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Simultaneously, glucose utilization in peripheral tissues is also persistently high. Despite mitochondrial function being compromised, activated immune cells, as well as the myocardium and brain, maintain glucose consumption, which, in many ways, occurs through anaerobic glycolysis.7,17,18 The liver does not have a comparable ability to recycle lactate via the Cori cycle, as enzyme activity is less active in sepsis, along with dysfunction of the mitochondria. Therefore, although glucose production is ultimately diminished, lactate accumulates as a secondary effect.7,19 Both of these occurrences account for the combination of dysglycemia and hyperlactatemia in an individual with late septic shock.

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Both ends of dysglycemia are detrimental clinically. Severe hyperglycemia worsens the infection and the endothelial dysfunction associated with it, while hypoglycemia is much more frequently associated with mortality.4 In observational studies in human septic patients, spontaneous hypoglycemia has been reported to confer nearly double the mortality compared with patients with treated hypoglycemia or who remained normoglycemic. In mouse experiments, a causal contribution was observed: glucose administration at the appropriate time or pharmacologic induction of moderate hyperglycemia during the hypometabolic period was associated with improved survival, likely by preventing catastrophic energy depletion in essential organs.5 These studies emphasize that euglycemia in sepsis is not just the application of insulin but also requires avoidance of hepatic glucose output suppression and preservation of hormonal support of gluconeogenesis.

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Circadian and nutritional factors further complicate the understanding of metabolism. Recent mouse studies reveal that the timing of septic insults relative to feeding–fasting cycles affects glycemic trajectories and survival. Sepsis during fasting contributes to more profound hypoglycemia and higher mortality, and these effects depend on hepatocyte clock genes such as Bmal1.20 These results suggest that nutritional principles and timing of nutrition may impact the body's metabolic tolerance to sepsis. However, the best strategies for application in human studies remain to be discovered.

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Mitochondrial dysfunction and bioenergetic failure

Mitochondria integrate endocrine and metabolic signals into ATP production. In sepsis, impaired oxygen delivery due to microcirculatory dysfunction is exacerbated by intrinsic mitochondrial dysfunction, creating "cytopathic hypoxia" in which cells cannot utilize oxygen even when it is present.7,8,21 Early sepsis is associated with mitochondrial structural injury, loss of mitochondrial DNA, and decreased oxidative phosphorylation capacity, as measured in several mouse models.8,9 Direct respirometry shows decreased ADP-stimulated (state 3) respiration and increased proton leak, which indicates both a quantitative and qualitative impairment of oxidative phosphorylation.9,21,22

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Several mechanisms contribute to this dysfunction. Reactive oxygen and nitrogen species can damage mitochondrial membranes and proteins. Additionally, pyruvate dehydrogenase kinase is up-regulated, inactivating the pyruvate dehydrogenase complex and reducing the amount of glycolytic carbon entering the tricarboxylic acid cycle.21,22 Furthermore, transcriptional regulators of mitochondrial biogenesis and fatty acid oxidation, such as PPAR-α and PGC-1α, are inhibited, leading to impaired β-oxidation and accumulation of lipid intermediates.10,23,24 Collectively, these changes will drive the cellular metabolism to anaerobic glycolysis and lactate production even in the presence of oxygen.

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The consequences of mitochondrial failure have multiple implications for cortico–metabolic adaptation. Most importantly, gluconeogenesis is an ATP-intensive process that relies on intact mitochondrial function in hepatocytes.9,25 Therefore, when oxidative phosphorylation is impaired, the liver is not able to compensate for glucose output in the presence of hormonal stimulation, which may predispose the individual to hypoglycemia. Second, the loss of ATP has profound effects on ion pumps and contractile function in high-workload metabolic organs, such as the heart, kidney, and diaphragm, leading to organ failure even in the absence of inflammatory injury.21,26 Lastly, lactate and increased protons may drive systemic metabolic acidosis, which can compound depressed myocardial performance and blunt responses to catecholamines and glucocorticoids.19

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Importantly, mitochondrial dysfunction in sepsis appears at least partly reversible. Experimental interventions that support mitochondrial function - antioxidants to limit ROS-mediated damage, thiamine to reactivate pyruvate dehydrogenase, and agents promoting mitochondrial biogenesis - can improve ATP content, reduce lactate, and increase survival in septic rodents.10,16,27 The proposed "metabolic resuscitation" strategy combining hydrocortisone, vitamin C, and thiamine is a translational example that aims to restore glucocorticoid signaling and mitochondrial enzymatic function simultaneously.10,12,24 Although clinical data remain mixed, these approaches highlight mitochondria as a promising therapeutic target that directly intersects with endocrine and metabolic pathways.

 

Integration of murine and human data on dysglycemia and outcome

Studies of mice show a consistent pattern of biphasic glycemia: hyperglycemia early due to stress and late hypoglycemia that closely precedes death.3,5,6 This pattern correlates with human data from extensive cohort clinical studies. In these cohorts, spontaneous hypoglycemia at admission, or during the week worked with early ICU admission, is consistently correlated with excess mortality and likely markers of more advanced metabolic decompensation.4 These clinical observations are further supported by older mechanistic studies showing that impaired hepatic glucose production is responsible for hypoglycemia that occurs in genetically or metabolically compromised mice,25 and in experimental studies of sepsis, exogenous glucose administration in late sepsis sometimes rescues survival.5,6

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Recent examinations of metabolic alterations in sepsis indicate that dysglycemia results from a complex interplay of increased glucose production, heterogeneous insulin resistance, and decreased peripheral utilization over the course of the illness.3,10,15,26 Our summary extends these frameworks by describing hypoglycemia as a downstream effect of combined adrenal, hepatic, and mitochondrial dysfunction rather than solely as a glycemic abnormality.

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Cortisol biology, CIRCI, and glucocorticoid resistance

Glucocorticoids may serve a dual purpose in sepsis by regulating excessive inflammation and maintaining vascular tone, while also supporting gluconeogenesis and substrate mobilization.1,2 Human and animal studies have documented relative adrenal insufficiency and tissue glucocorticoid resistance (GCR) in severe sepsis, and both are associated with adverse outcomes.1,14,24,26 A central study in murine models demonstrated that combined GR dysfunction and hyperlactatemia promoted a lethal vascular phenotype characterized by extreme hypotension, vascular leak, and organ failure despite systemic glucocorticoid levels being markedly elevated.7 This analysis helps illustrate that physiologic availability of the glucocorticoid is not sufficient and that receptors are poorly signaling downstream from the ligand-binding region.

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More recent research has expanded this perspective by including sepsis-associated endocrine alterations within a broader evaluation of systemic inflammation and stress metabolism.1,26 Reviews of CIRCI conclude that altered cortisol synthesis, increased turnover, and target-tissue resistance may coincide, complicating the interpretation of routine endocrine tests and possibly underestimating the effect of functional glucocorticoid deficiency.24,26 The experimental data referenced here suggest that when compromised GR signaling is specifically at play, the capacity for hepatic gluconeogenesis is particularly compromised, easing the transition from stress hyperglycemia to catastrophic hypoglycemia - especially with a reduced intake of nutritional substrate.1-3,7,25,26

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Mitochondrial failure as a corresponding downstream mechanism

Mitochondrial dysfunction is another recurring overall theme that connects endocrine, immunologic, and metabolic observations in sepsis. Both mechanistic review articles and experimental research describe reduced oxidative phosphorylation, diminished electron transport chain activity, and alterations in mitochondrial biogenesis in multiple organs, including the liver, heart, skeletal muscle, and diaphragm.7,8,17,22 Cardiac-focused research demonstrates that sepsis-related differences in cardiomyocyte mitochondrial mono-ADP-ribosylation may determine the heart's ability to maintain bioenergetic reserves and, therefore, exacerbate survival vs. non-survival.8,27 Likewise, in the field of skeletal muscle and respiratory muscle research, mitochondrial injury may contribute to both weakness and impaired weaning or recovery.15,19

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These mitochondrial modifications directly impact glucose homeostasis. Gluconeogenesis in the liver requires considerable ATP, and oxidative phosphorylation cannot be effectively restored with intact hormone stimulation from glucagon, glucocorticoids, etc.7,8,22 Mitochondrial support for glucose production comes from oxidative phosphorylation. Therefore, because excessive acetyl-CoA enters the tricarboxylic acid (TCA) cycle and pyruvate is diverted away from glucose production, overstimulation of pyruvate dehydrogenase kinase and impaired PDH activity divert pyruvate away from the TCA cycle, leading to excess lactate production and contributing to hyperlactatemia in advanced sepsis.7,15,21,22 Last, changes in lipid oxidation, new roles of UCP2, and other mitochondrial regulators suggest that sepsis induces a maladaptive metabolic reprogramming that favors glycolysis and lactate formation over ATP production.1,9,11,13,20

 

Therapeutic implications and translational relevance

The integrated model of cortico–metabolic failure has meaningful translational implications. First, it provides a mechanistic basis for sudden hypoglycemia in septic patients, being a strong negative prognostic marker, and should be interpreted as more than just a side effect of either insulin therapy or inferior nutritional intake. Still, as a signal of apparent advanced endocrine–metabolic failure in the septic system.3,4,15,26 Clinically, this reinforces the importance of close glucose monitoring and a more fine-tuned approach to glycemic control to avoid hyperglycemia, which can be harmful, or relative overuse of medical insulin therapy, in medium- to high-risk metabolic fragile patients.

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Secondly, these data justify revisiting adjunctive corticosteroid therapy and highlight the importance of timeliness, dosing, and patient selection. Although hydrocortisone remains contentious in sepsis, experimental data suggest that the benefit is mainly observed within a time window when GR signaling is partially intact and mitochondrial function is at least partially reversible.1,2,7,12,26 Future strategies could use GR-sensitizing approaches or pharmacologic agents that specifically activate GR-induced downstream processes (e.g., GILZ and other cytoprotective molecules).7,26

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Thirdly, the increasing interest in metabolic resuscitation and the use of mitochondria-targeted resuscitation strategies (thiamine, vitamin C, mitochondria-targeted antioxidants, dichloroacetate (DCA), metformin, and UCP2 modulators) provide potential new treatment targets.1,8-11,16,17,20-22 DCA, for example, can reactivate PDH, restoring pyruvate flux into the TCA cycle, decreasing lactate production, and improving hepatic and cerebral metabolism in septic models.21,22 Metformin, an agent traditionally considered an antihyperglycemic drug, has recently demonstrated immunomodulatory and mitochondrial effects that could be useful in the management of sepsis when administered at specific doses.11,16 Drugs targeting UCP2 and/or lipid oxidation pathways hold additional promise for modulating metabolic reprogramming as a treatment target, rather than solely for hemodynamic effects or pathogen eradication.1,11,20

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Fourth, research from murine models assessing the effects of feeding status, circadian biology, and baseline metabolic phenotype indicates that the host metabolic context influences the overall trajectory of sepsis.6,9,10,15,26 These observations could provide the basic framework for a precision nutrition approach, individualized nutritional support, feeding schedule, and glycemic target, although there is still a relative lack of patient data.

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Limitations of current evidence and future research directions

It is important to note some limitations. A large proportion of the experimental studies discussed use specific murine strains, standardized experimental models (such as CLP or endotoxemia), and conditions that do not adequately reflect the heterogeneity of human sepsis.5,7,9,15,22 The differences in immune ontogeny, metabolic rate, and HPA axis regulation between species limit a direct translation of findings.1,2,26 Further, several of the mechanistic perspectives presented are still derived from earlier foundational work (for example, C/EBPβ deletion models) that precede modern definitions of sepsis, but are still pertinent to understanding hepatic and endocrine physiology.25

CONCLUSIONS

The elevated mortality associated with septic shock is indicative of defects in multiple mutually reinforcing compensatory homeostatic systems. Research in experimental murine models over the past five years has clarified how failure of cortico–metabolic adaptation reflects a breakdown of these compensatory systems. For example, heightened glucocorticoid resistance due to hypothalamic-pituitary-adrenal axis dysfunction deprives the host of key anti-inflammatory and gluconeogenic signals. Inhibition of hepatic gluconeogenesis due to systemic inflammation and glycogen depletion further facilitates increased peripheral glucose utilization, leading to critical illness hypoglycemia, commonly accompanied by hyperlactatemia. Mitochondrial dysfunction further decreases metabolic efficiency, promoting organ failure, driving additional immunometabolic dysfunction, and rendering circulating hormones ineffective.

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All of this data suggests that optimal management of sepsis must expand beyond solely controlling the infection and providing hemodynamic support to include integrating protective care. Maintaining and, when necessary, supplementing optimal adrenal function, maintaining hepatic glucose production, avoiding excessive fasting protocols, and viably supporting mitochondrial health represent reasonable components of a plan to sustain bioenergetic homeostasis and limit bioenergetic collapse. Mechanistic murine models provide a valuable platform for testing these interventions and serve as an arena for exploring new therapeutic mechanisms, such as glucocorticoid receptor sensitizers, enhanced pyruvate dehydrogenase function, and targeted mitochondrial-protective antioxidant mechanisms. Transitioning these insights to the realities of human medicine, where precisely timed, need-based interventions remain a significant obstacle, our understanding of the mechanisms of cortico–metabolic dysfunction brings these considerations closer to reality.

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Another important limitation is that most animal model interventions are delivered at precisely timed intervals relative to sepsis onset. In contrast, human patients tend to present at variable and often late stages of disease. Machine-learning analytics, along with nuanced staging of the sepsis trajectory, may help align preclinical interventions with clinically relevant time windows, but this is an emerging field of study. Finally, while interest in the concept of metabolic resuscitation is increasing, there is a lack of large and well-conducted clinical trials that can disentangle which patient subgroups respond best to which metabolic interventions (e.g., corticosteroids, thiamine, vitamin C, PDH activators, mitochondrial targeted therapies), and many of the studies conducted will likely lack sufficient power.

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Despite these limitations, the convergence of animal and clinical studies provides substantial supporting evidence for the central hypothesis of this review: failure of cortico–metabolic adaptation is an important, and potentially modifiable, determinant of outcomes following septic shock. Future studies in the field should prioritize integrative experimental designs that incorporate endocrine-, metabolic, mitochondrial-, and immunologic-based readouts in assessments of experimental animal models and carefully phenotyped human cohorts. Completing this work will allow these mechanistic insights to be transitioned into personalized metabolic interventions for sepsis, appropriately timed to the phase of the disease course.

AUTHOR AFFILIATION

1 Pathophysiology Department, Tbilisi State Medical University (TSMU), Tbilisi, Georgia;

2 National Institute of Endocrinology, Tbilisi, Georgia.

REFERENCES

  1. Mehdi SF, Qureshi MH, Pervaiz S, et al. Endocrine and metabolic alterations in response to systemic inflammation and sepsis: a review article. Mol Med. 2025;31(1):16. doi:10.1186/s10020-025-01074-z.

  2. Vandewalle J, Libert C. Glucocorticoids in sepsis: to be or not to be. Front Immunol. 2020;11. doi:10.3389/fimmu.2020.01318.

  3. Wasyluk W, Zwolak A. Metabolic alterations in sepsis. J Clin Med. 2021;10(11):2412. doi:10.3390/jcm10112412.

  4. Mitsuyama Y, Shimizu K, Komukai S, et al. Sepsis-associated hypoglycemia on admission is associated with increased mortality in intensive care unit patients. Acute Med Surg. 2022;9(1). doi:10.1002/ams2.718.

  5. Sung-Su K, Yun-Beom S, Soo-Hyun P. Effect of D-glucose feeding on mortality induced by sepsis. ResearchGate. Published June 4, 2025. doi:10.4196/kjpp.2016.20.1.83.

  6. Liu HY, Wen GB, Han J, et al. Inhibition of gluconeogenesis in primary hepatocytes by stromal cell-derived factor-1 (SDF-1) through a c-Src/Akt-dependent signaling pathway. J Biol Chem. 2008;283(45):30642. doi:10.1074/jbc.M803698200.

  7. Vandewalle J, Timmermans S, Paakinaho V, et al. Combined glucocorticoid resistance and hyperlactatemia contributes to lethal shock in sepsis. Cell Metab. 2021;33(9):1763-1776.e5. doi:10.1016/j.cmet.2021.07.002.

  8. Nuyttens L, Heyerick M, Heremans G, et al. Unraveling mitochondrial pyruvate dysfunction to mitigate hyperlactatemia and lethality in sepsis. Cell Rep. 2025;44(8). doi:10.1016/j.celrep.2025.116032.

  9. Stolarski AE, Kim J, Rop K, Wee K, Zhang Q, Remick DG. Machine learning and murine models explain failures of clinical sepsis trials. J Trauma Acute Care Surg. 2022;93(2):187. doi:10.1097/TA.0000000000003691.

  10. Mottale R, Dupuis C, Szklarzewska S, Preiser JC. The metabolic response to stress in critical illness: updated review on the pathophysiological mechanisms, consequences, and therapeutic implications. Ann Intensive Care. 2025;15(1):174. doi:10.1186/s13613-025-01588-z.

  11. Muniz-Santos R, Lucieri-Costa G, Almeida MAP de, et al. Lipid oxidation dysregulation: an emerging player in the pathophysiology of sepsis. Front Immunol. 2023;14. doi:10.3389/fimmu.2023.1224335.

  12. Fowler C, Raoof N, Pastores SM. Sepsis and adrenal insufficiency. J Intensive Care Med. 2023;38(11):987-996. doi:10.1177/08850666231183396.

  13. Yap JQ, Nikouee A, Lau JE, Walsh G, Zang QS. Mitochondria at the heart of sepsis: mechanisms, metabolism, and sex differences. Int J Mol Sci. 2025;26(9):4211. doi:10.3390/ijms26094211.

  14. Hao D, Wang Q, Ito M, et al. The ACTH test fails to diagnose adrenal insufficiency and augments cytokine production in sepsis. JCI Insight. 2025;10(8). doi:10.1172/jci.insight.187487.

  15. Xiao M, Liu D, Xu Y, Mao W, Li W. Role of PFKFB3-driven glycolysis in sepsis. Ann Med. 2023;55(1):1278-1289. doi:10.1080/07853890.2023.2191217.

  16. Xu J, Wang J, Zhao M, Li C, Hong S, Zhang J. LncRNA LINC01018/miR-942-5p/KNG1 axis regulates the malignant development of glioma in vitro and in vivo. CNS Neurosci Ther. 2023;29(2):691-711. doi:10.1111/cns.14053.

  17. Pierre A, Favory R, Brassart B, et al. Sepsis induces long-term muscle and mitochondrial dysfunction due to autophagy disruption amenable by urolithin A. J Cachexia Sarcopenia Muscle. 2025;16(4):e70041. doi:10.1002/jcsm.70041.

  18. Yu X, Hu X, Wang D, et al. Macrophage S1PR2 drives sepsis-induced immunosuppression by exacerbating mitochondrial fragmentation. Am J Respir Cell Mol Biol. 2025;72(6):615-626. doi:10.1165/rcmb.2024-0161OC.

  19. Supinski GS, Wang L, Schroder EA, Callahan LAP. SS31, a mitochondrially targeted antioxidant, prevents sepsis-induced reductions in diaphragm strength and endurance. J Appl Physiol. 2020;128(3):463-472. doi:10.1152/japplphysiol.00240.2019.

  20. Li N, Deng J, Zhang J, et al. A new strategy for targeting UCP2 to modulate glycolytic reprogramming as a treatment for sepsis. Inflammation. 2024;47(5):1634-1647. doi:10.1007/s10753-024-01998-4.

  21. Ji L, He Q, Liu Y, et al. Ketone body β-hydroxybutyrate prevents myocardial oxidative stress in septic cardiomyopathy. Oxid Med Cell Longev. 2022;2022(1):2513837. doi:10.1155/2022/2513837.

  22. Hu D, Sheeja Prabhakaran H, Zhang YY, Luo G, He W, Liou YC. Mitochondrial dysfunction in sepsis: mechanisms and therapeutic perspectives. Crit Care. 2024;28(1):292. doi:10.1186/s13054-024-05069-w.

  23. Sulzbacher MM, Sulzbacher LM, Passos FR, et al. Adapted murine sepsis score: improving the research in experimental sepsis mouse model. Biomed Res Int. 2022;2022(1):5700853. doi:10.1155/2022/5700853.

  24. Sobolewska J, Dzialach L, Kuca P, Witek P. Critical illness-related corticosteroid insufficiency (CIRCI): an overview of pathogenesis, clinical presentation, and management. Front Endocrinol. 2024;15. doi:10.3389/fendo.2024.1473151.

  25. Liu S, Croniger C, Arizmendi C, et al. Hypoglycemia and impaired hepatic glucose production in mice with a deletion of the C/EBPbeta gene. J Clin Invest. 1999;103(2). doi:10.1172/JCI4243.

  26. Liu J, Zhou G, Wang X, Liu D. Metabolic reprogramming consequences of sepsis: adaptations and contradictions. Cell Mol Life Sci. 2022;79(8):456. doi:10.1007/s00018-022-04490-0.

  27. Chen X, Yuan T, Zheng D, et al. Cardiomyocyte mitochondrial mono-ADP-ribosylation dictates cardiac tolerance to sepsis by configuring bioenergetic reserve in male mice. Nat Commun. 2025;16(1):8119. doi:10.1038/s41467-025-62384-8.

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