Critical illness represents one of the major challenges of contemporary medicine, with sepsis standing out as one of its most complex and prevalent manifestations, responsible for countless deaths worldwide. Defined by the Sepsis-3 consensus as a life-threatening organ dysfunction caused by a dysregulated host response to infection, it is estimated to account for approximately 20% of global deaths, maintaining a guarded prognosis despite advances in therapy. Its most severe form, septic shock, is defined by the need for vasopressors to maintain a mean arterial pressure (MAP) ≥ 65 mm Hg and a serum lactate level greater than 2 mmol/L despite adequate fluid resuscitation and is associated with significantly higher mortality.

The pathophysiology of sepsis has historically been conceptualized as a sequence of phases: a proinflammatory peak followed by compensatory immunosuppression. However, current models propose that hyperinflammation and immunosuppression coexist simultaneously across different biological compartments and even within the same tissue. This overlap promotes multiple organ dysfunction syndrome (MODS), and in survivors of the acute phase, may evolve into persistent inflammation, immunosuppression, and catabolism syndrome (PICS), a state of chronic vulnerability associated with high subacute/chronic mortality. ^, Metabolic reprogramming has emerged as a central axis for the pathophysiology of sepsis: beyond serving as energy sources, metabolites act as regulators of interorgan communication. Host survival depends on the balance between mechanisms of resistance and disease tolerance, which is often impaired and leads to high morbidity and mortality.

Given the clinical heterogeneity and the immunometabolic complexity of this syndrome (which serves as an umbrella term for a vast array of pathology), here we analyze the pathophysiological mechanisms of sepsis, integrating the coexistence of opposing immune states, the signaling role of metabolism, and emerging clinical diagnostic metrics and therapeutic targets.

Historically, the pathophysiology of sepsis has been focused almost exclusively on resistance . This is the host’s ability to detect, engage, and eliminate pathogens through the activation of classic immune effector responses. This defense strategy is energetically very demanding and often leads to collateral tissue damage and the development of MODS. A critical, emerging paradigm is disease tolerance : the host’s ability to maintain physiologic function and survive an infectious burden without necessarily reducing the pathogen load. The metabolic reprogramming observed in sepsis might not merely be a failure of bioenergetics, but a potential adaptive mechanism to preserve cell viability under extreme stress. Survival to sepsis may rely on a dynamic and delicate balance between resistance (driven by rapid metabolic shifts that support high-energy effector functions to clear the pathogen) and disease tolerance (characterized by a quiescent metabolic state that minimizes oxidative damage and prevents the transition from reversible organ dysfunction to permanent failure). Reframing sepsis through the lens of disease tolerance allows us to better understand the immunometabolic double-edged sword . Therapeutic success may depend not just on how well we assist the host in fighting the pathogen, but on how effectively we support the metabolic pathways that protect the host from its own dysregulated immune response.

The key definitions in this essay reflect the evolution from earlier consensus frameworks—Sepsis-1 and Sepsis-2, which centered on the systemic inflammatory response syndrome (SIRS)—toward the current Sepsis-3 paradigm, which repositions organ dysfunction as the defining feature of the syndrome and leaves the concept of SIRS behind. Throughout this article, sepsis and septic shock are defined and described according to the Sepsis-3 criteria, with organ dysfunction quantified by the Sequential Organ Failure Assessment (SOFA) score incorporating the 2025 update, and the Phoenix Sepsis Score applied where the pediatric population is specifically considered. MODS and the immunosuppressive component of the host response—historically termed compensatory anti-inflammatory response syndrome (CARS), though increasingly framed within the broader concept of sepsis-induced immune dysregulation—are introduced in the following subsections as the principal syndromic expressions of the pathophysiological processes this article examines.

MODS: It is the clinical expression of a sustained and dysregulated response of the host to a stressor, leading to the progressive failure of 2 or more organ systems. It develops when the body can no longer properly control its response to a major insult, involving complex interactions between the immune system, the endothelium, metabolism, and coagulation, leading to a loss of response regulation and ultimately gravely affecting the host’s tissues. While it is most commonly associated with sepsis, MODS can also occur in noninfectious conditions such as noninfectious shock, severe trauma, acute pancreatitis, or extensive burns, among many other scenarios. Its pathophysiology is complex and not yet fully understood. Rather than being simply a state of excessive inflammation, MODS reflects a dynamic imbalance between proinflammatory and anti-inflammatory processes, which often occur simultaneously. Key mechanisms include endothelial dysfunction, microcirculatory impairment, immune dysregulation, mitochondrial dysfunction, and disturbances in coagulation. In addition, factors such as pathogen-derived endotoxins and the translocation of gut bacteria and toxins into the bloodstream can further drive disease progression. Together, these processes impair tissue perfusion and cellular function, ultimately leading to organ failure—mechanisms that will be explored in more detail in the following sections.

CARS and PICS: CARS is an immunosuppressive state that occurs in sepsis, characterized by profound immune dysfunction. Although classically described as following SIRS (in the biphasic model of immune activity in sepsis), current consensus is that it occurs alongside hyperinflammatory states in the host. Over time, this condition has been characterized by features such as cutaneous energy, lymphocyte depletion through apoptosis, reduced cytokine production by monocytes in response to stimulation, decreased expression of human leukocyte antigen (HLA) antigen–presenting molecules on monocytes, and increased production of anti-inflammatory cytokines such as interleukin-10 (IL-10). At this point, the individual enters a stage of relative immunosuppression, becoming susceptible to secondary or nosocomial infections, thus perpetuating the sepsis cascade and possibly leading to his death.

PICS: It refers to a prolonged clinical phenotype in which patients present low-grade chronic inflammation, persistent immunosuppression (with associated recurrent infections and prolonged hospital stays) and a catabolic metabolism resulting in, among other phenomena, severe sarcopenia. It is thought of as a long-term consequence of an ill-resolved septic episode and can cause severe morbidity and mortality, and its self-perpetuating nature poses severe challenges to its treatment.

Immune Responses Initiation: The recognition of the infectious agent constitutes the initial and determining event in the pathophysiology of sepsis, establishing the transition from a localized infection to a dysregulated systemic inflammatory response, which is what usually poses a fatal threat to the host. Although classically centered on the detection of microbial components, the current paradigm acknowledges that this process involves a complex integration of signals derived from the pathogen, the host, and disturbances in cellular homeostasis, followed by profound metabolic and functional reprogramming. The simple recognition of a pathogen by immune cells as the starting point is not only too simplistic as it is often simply not the case.

The Signal Triad : Pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and homeostasis-altering molecular processes (HAMPs): The primary initial stimuli are PAMPs, conserved microbial structures—such as bacterial lipopolysaccharide, viral RNA, or fungal β-glucans. These are recognized by pattern recognition receptors (PRRs), notably toll-like receptors, nucleotide-binding oligomerization domain (NOD)-like receptors, and retinoic acid-inducible gene- I (RIG-I)-like receptors ( Fig. 1 ). Activation of these receptors triggers intracellular signaling cascades, centered on pathways such as nuclear factor-κB (NF-κB) and MAP kinases, culminating in the nuclear genetic transcription of pro-inflammatory cytokines and mediators of the innate immune response.

Pathogen recognition and early immune signaling in sepsis. PRRs on innate immune cells, including toll-like receptors and NOD-like receptors sense PAMPs on invading microorganisms. This recognition triggers intracellular signaling cascades that activate transcription factors such as NF-κB and interferon regulatory factors (IRFs), and lead to the production of proinflammatory cytokines, chemokines, and interferons. The resulting response promotes pathogen clearance but may contribute to systemic inflammation and organ dysfunction characteristic of sepsis. Created using Inkscape.

However, the inflammatory response is not strictly exogenous. Infection-induced tissue injury releases damage-associated molecular patterns (DAMPs), such as mitochondrial DNA, histones, and heat shock proteins. These endogenous agonists amplify immune activation through the same PRRs, establishing a self-propagating inflammatory feedback loop. This way, our threat sensors not only react to external pathogens that may pose a threat to the individual but also to actual signs of cellular damage. A critical event at this stage is the activation of the NLRP3 inflammasome, which processes pro-interleukin-1β (IL-1β) and pro-interleukin-18 into their active forms and may induce pyroptosis, a highly inflammatory form of programmed cell death that exacerbates the progression of organ dysfunction.

More recently, the concept of HAMPs has redefined surveillance immunity. HAMPs are not discrete molecules but rather states of functional deviation—such as mitochondrial dysfunction, endoplasmic reticulum stress, and inhibition of protein synthesis. The detection of these alterations, frequently involving cellular stress-response pathways such as the integrated stress response, allows the immune system to monitor and fine-tune the magnitude of its response by integrating signals of perceived damage with the presence of a pathogen, thereby perfecting the response, although sepsis is one of many examples of this system leading to deleterious consequences on the host. This way, the current signaling model includes molecular patterns associated with pathogens, with host damage and with actual states of functional change, reflecting the nuanced and highly detailed mechanism of danger recognition and response.

Cellular Interactions and Immunometabolism: The recognition of these previously described danger signals extends beyond classical immune cells. While macrophages and dendritic cells act as early sentinels (given their initial role as antigen-presenting cells), the recruitment of neutrophils introduces potent amplification mechanisms, including the release of reactive oxygen species (ROS) and the formation of neutrophil extracellular traps (NETs). Although essential for controlling microbial burden, NETs exert direct cytotoxic effects on the endothelium and promote immunothrombosis, representing a critical interface between innate immunity and vascular injury, exemplifying the somewhat maladaptive nature of many of these responses in extreme scenarios such as sepsis; vascular injury being absolutely essential in the symptomatic changes of septic shock (such as increased vascular permeability, relative hypovolemia, and effective hypotension), this response is highly mechanistically important.

The calibration of immune response magnitude described above is inseparable from the metabolic state of the cells executing it. Immunometabolism—the study of how metabolic programs shape and are shaped by immune function—has emerged as a central organizing framework in sepsis research, both for understanding host damage and for identifying therapeutic targets. Instead, recognition of these signals induces profound intracellular metabolic reprogramming, which deeply shapes and determines the nature, magnitude, and duration of the inflammatory response that the cells then promote. Understanding these metabolic changes is crucial for evaluating and predicting the host’s response to a given stressor, despite its obvious challenges.

This reprogramming operates through specific metabolic intermediates that function as direct mediators of intercellular communication and immune regulation. Metabolism exists beyond simple processes for energy supply and usage and is critical for appropriate cell-to-cell communication and coordinating responses. Succinate, released from mitochondria under inflammatory conditions, stabilizes HIF-1α and amplifies IL-1β production in macrophages. Itaconate, derived from the Krebs cycle, acts as a counter-regulatory signal, suppressing proinflammatory gene expression and modulating oxidative stress. Lactate, beyond its clinically vital role as a metabolic substrate and indicator of hypoperfusion, influences macrophage polarization and T-cell function, connecting the bioenergetic state of the cell to its immunologic output. These relationships establish an indissociable link between the metabolic state of immune cells, the nature of the host response, and the clinical phenotype of sepsis—a link that becomes particularly consequential in the context of the simultaneous hyperinflammatory and hypoinflammatory states that characterize the syndrome, and which will be explored in detail in subsequent sections.

Endothelial dysfunction and microcirculation: Endothelial dysfunction represents a central component in the pathophysiology of sepsis, constituting a critical junction between systemic inflammatory activation and progression to multiorgan failure. Far from being a passive mechanical barrier, the endothelium functions as a dynamic organ with immunologic, metabolic, and hemostatic properties. During systemic infection, profound endothelial reprogramming plays a decisive role in the loss of vascular homeostasis, with very consequential effects on the whole immune response.

Endothelial activation is triggered early by exposure to PAMPs and DAMPs, which are recognized by PRRs expressed on endothelial cells. This response is further amplified by proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) and IL-1β, driving a phenotypic transition. Activated endothelial cells upregulate adhesion molecules, produce inflammatory mediators, and actively modulate vascular tone and coagulation pathways. While this activated state contributes to pathogen containment, it simultaneously initiates maladaptive alterations in systemic vascular regulation. In a way, this is the natural story of the immune response in sepsis: although adaptive at first, its dysregulation and consequences result in life-threatening danger to the host.

One of the earliest consequences of this phenotypic endothelial reprogramming is the disruption of endothelial barrier integrity. This process frequently begins with shedding of the endothelial glycocalyx, a proteoglycan-rich luminal layer that plays a key role in mechano-transduction and permeability regulation. Glycocalyx degradation, alongside the disorganization of cell-to-cell junctions, results in a marked increase in vascular permeability. The ensuing extravasation of fluid into the interstitial space leads to diffuse tissue edema, a reduction in effective intravascular volume, and impaired oxygen diffusion to tissues, with the characteristic hypotension leading to severe tissue hypoxia and eventually shock.

Concurrently, a profound dysregulation of the vascular tone develops, characterized by excessive production of nitric oxide and other vasodilatory mediators. The result is systemic vasodilation with reduced peripheral vascular resistance resulting in hypotension. This state is compounded by vascular hyporesponsiveness to catecholamines, reflecting a failure of both endogenous and exogenous vasoconstrictive mechanisms and interconnecting vascular collapse with endocrine changes. This phenomenon represents a key pathophysiological hallmark of septic shock (hence its alternative name vasoplegic shock ) and critically limits hemodynamic compensation. Many of the problems in the medical management of septic shock are caused not only by the affected vascular tone but fundamentally from the vascular tissues hyporesponsiveness.

In parallel, the endothelium acquires a procoagulant phenotype, characterized by increased expression of tissue factor and inhibition of physiologic anticoagulant and fibrinolytic pathways. These changes promote the formation of microthrombi within the capillary network, leading to obstruction of the microcirculation. Consequently, a dissociation between macrocirculatory parameters and effective tissue perfusion emerges, whereby systemic hemodynamic variables may appear stabilized despite persistent and heterogeneous microvascular dysfunction. This is the way DIC is so common in septic shock.

The combined effects of increased permeability, vasoplegia, and microvascular thrombosis culminate in impaired oxygen delivery and utilization at the cellular level. This condition, often referred to as cytopathic hypoxia, is frequently associated with mitochondrial dysfunction, in which cells are unable to effectively utilize available oxygen for energy production. In addition, the injured endothelium acts as an amplifier of the inflammatory response by facilitating leukocyte recruitment and promoting further release of DAMPs, thereby contributing to a self-sustaining cycle of inflammation. This persistent inflammatory state may subsequently transition into prolonged immunosuppression, contributing to increased susceptibility to secondary infections and adverse clinical outcomes.

From an integrative perspective, endothelial dysfunction represents a pivotal transition from adaptive host defense mechanisms toward a maladaptive systemic response. When endothelial activation becomes excessive or sustained, the failure to restore vascular homeostasis drives the progression to multiorgan dysfunction. Thus, the endothelium is not merely a passive bystander in sepsis but an active mediator linking the initial infectious insult to the circulatory and metabolic failure that defines its most severe forms and eventually leads to catastrophic consequences on the host.

Mitochondrial dysfunction represents a critical node in the pathophysiology of sepsis, linking microcirculatory disturbances to cellular bioenergetic failure and exemplifying how sepsis, rather than simply a systemic disturbance, causes and is caused by severe cellular dysfunction. Rather than a passive consequence of critical illness, it is increasingly recognized as a central component of immunometabolic reprogramming that influences both immune responses and organ function—and contributes to the multi-organ dysfunction and excess mortality that characterize the most severe presentations of the syndrome.

During early sepsis, inflammatory signaling induces a shift toward aerobic glycolysis in immune cells, supporting rapid effector functions. This occurs alongside a reprogramming of mitochondrial metabolism, with reduced pyruvate oxidation and impaired oxidative phosphorylation. The resulting state—often termed cytopathic dysoxia—reflects a condition in which oxygen utilization for adenosine triphosphate (ATP) generation is compromised despite apparently adequate systemic delivery. This distinction is important: microcirculatory heterogeneity in sepsis means that regional oxygen availability is frequently impaired even when global delivery parameters appear preserved, and the two phenomena likely coexist and reinforce one another. Therefore, normal oxygenation patterns do not mean that there is no cellular damage. Mitochondrial dysfunction itself manifests through alterations in respiratory chain activity, loss of mitochondrial membrane potential, and reduced coupling efficiency—that is, increased proton leak relative to ATP production—ultimately leading to bioenergetic insufficiency. While challenging, this creates chances for drugs targeting mitochondria to be repurposed for sepsis if their effect helps fight back against this organelle’s dysfunction.

Sepsis also disrupts mitochondrial quality control. Excessive production of ROS, combined with impaired antioxidant defenses, promotes oxidative damage to mitochondrial components. Concurrently, mitochondrial dynamics shift toward fragmentation, while mitophagy—initially protective—becomes insufficient and impaired under sustained stress. Reduced mitochondrial biogenesis, partly linked to decreased expression of regulators such as PGC-1α, further contributes to the accumulation of dysfunctional organelles. Importantly, mitochondrial DNA released into the cytosol can act as a damage-associated molecular pattern, activating the cGAS–STING pathway and amplifying intracellular inflammatory signaling. When released into the extracellular space, it may engage TLR9 on immune cells, extending this proinflammatory signal to the systemic level. These mechanisms are complementary but distinct, and both appear operative in sepsis and working toward prolonging the response.

Importantly, mitochondrial dysfunction may not solely represent irreversible injury. In certain contexts, reduced mitochondrial activity appears to reflect an adaptive metabolic downregulation aimed at preserving cellular viability under stress. In organs such as the kidney, heart, and brain, this has been conceptualized as a reversible cellular shutdown , which may limit activation of apoptotic and potentially ferroptotic cell death pathways, allowing functional recovery following resolution of the septic insult. However, when prolonged or dysregulated, this adaptive response may itself become pathologic—contributing to persistent organ dysfunction, failure to recover renal tubular function, and the broader syndrome of chronic critical illness seen in patients who survive the acute phase but do not return to baseline organ function. The limit between the adaptive mitochondrial downregulation and the overly extensive harmful prolongation, although very nuanced and challenging, is nevertheless a potential target for study and therapeutics.

The transition from cellular biology to therapeutic implications is, in this domain, particularly consequential. Due to their bacterial ancestry, mitochondrial ribosomes are susceptible to inhibition by antibiotics targeting bacterial protein synthesis. Of the agents used to treat infection, oxazolidinones—linezolid in particular—carry the most well-established clinical signal of mitochondrial toxicity, primarily through inhibition of mitochondrial translation with prolonged use. Tetracyclines and macrolides share this theoretic susceptibility, but clinically relevant mitochondrial toxicity at standard exposures appears limited, and the risk should not be overstated for these classes before further studies. In all cases, the potential for mitochondrial effects is most relevant in the setting of prolonged exposure. Conversely, preclinical studies suggest that partial inhibition of mitochondrial function may induce adaptive stress responses, including mitohormesis, promoting cellular resilience. ^, While such effects remain experimental and have not been translated into clinical practice, they hold substantial potential.

Accordingly, antimicrobial therapy in sepsis should remain guided by established principles—early administration, appropriate coverage, and source control—rather than attempts to modulate mitochondrial function. Nevertheless, awareness of potential mitochondrial effects is clinically relevant in selected scenarios, most notably in patients with prolonged illness in whom persistent lactic acidosis despite adequate resuscitation and source control prompts consideration of a metabolic rather than purely circulatory etiology. Given the metabolic importance of mitochondria, it is critical to understand how these drugs affect this organelle.

Despite growing insights, key uncertainties persist. Mitochondrial dysfunction is consistently associated with disease severity, but its precise role—whether causal, contributory, or adaptive—remains context-dependent. Moreover, interventions targeting mitochondrial metabolism have shown biochemical improvements without consistent benefit in clinical outcomes. These findings highlight the heterogeneity of sepsis and underscore the need for biomarker-driven approaches to better define metabolic phenotypes and guide targeted therapies. Among the candidates under investigation, the lactate-to-pyruvate ratio, circulating mitochondrial DNA levels, NAD ⁺/NADH redox state, and plasma succinate have each demonstrated mechanistic relevance, though none has yet achieved validated clinical utility.

Immune reprogramming and immunosuppression —Host defense against infection involves a complex interplay between innate and adaptive immune responses, supported by the profound metabolic reprogramming as discussed above. Building on the established framework of PAMPs, DAMPs, and HAMPs recognition, what follows describes how the downstream immune response unfolds at the cellular level—and how the metabolic state of immune cells shapes its trajectory, magnitude, and ultimate consequences for the host.

In sepsis, immune cells—particularly leukocytes—mount an intense response aimed at rapid pathogen clearance. Activation of major inflammatory pathways, including NF-κB and the inflammasome, drives rapid cellular activation, proliferation, and the production of early proinflammatory cytokines including TNF-α, IL-1β, and interleukin-6 (IL-6). These processes impose substantial metabolic demands, driving increased glucose utilization and extensive remodeling of amino acid metabolism to sustain effector functions.

At the cellular level, this early response is characterized by a shift toward aerobic glycolysis and enhanced nutrient uptake—a state that prioritizes speed of activation over energetic efficiency. When sustained, this metabolic configuration contributes to mitochondrial dysfunction, impaired oxidative phosphorylation, and reduced fatty acid oxidation. The resulting decline in ATP availability, together with persistent inflammatory signaling, progressively impairs immune cell function and creates the conditions for the immunosuppressive transition described below.

Concurrently, regulatory mechanisms are activated to limit excessive inflammation. These include the upregulation of anti-inflammatory mediators such as IL-10 and transforming growth factor-β, immune cell reprogramming, lymphocyte apoptosis, dendritic cell dysfunction, and increased expression of immune checkpoint molecules—notably PD-1 and PD-L1—which attenuate T-cell activation and have emerged as relevant therapeutic targets in the context of sepsis-induced immunosuppression. Collectively, these processes contribute to a state of impaired pathogen clearance and increased susceptibility to secondary and nosocomial infections. Both sides of this immune double edge sword pose a significant threat to the host but nevertheless offer therapeutic options.

Importantly, contemporary models reject the notion of a strictly sequential transition from hyperinflammation to immunosuppression. Instead, these processes occur simultaneously across different biological compartments, reflecting a dynamic and dysregulated host response in which inflammatory and anti-inflammatory pathways coexist and interact throughout the course of the illness, in different organs and tissues at the same time.

Neuroendocrine Axis: Sepsis both affects and is influenced by the neuroendocrine system, reflecting a tightly integrated and bidirectional interplay between inflammation and hormonal regulation. This interaction is inseparable from the immunometabolic reprogramming described above: inflammatory mediators disrupt hormonal signaling pathways, while neuroendocrine alterations reciprocally modulate immune cell function and systemic metabolic homeostasis. Microbial products and cytokine signaling profoundly reshape the host endocrine profile, contributing to global physiologic dysregulation and organ dysfunction. Accordingly, the identification of biomarkers that capture this axis—such as copeptin, a surrogate marker of vasopressin secretion—represents a promising approach for improved risk stratification in severe illness.

At a mechanistic level, sepsis disrupts neuroendocrine function through both intracellular signaling alterations and intercellular dysregulation across endocrine axes. Proinflammatory cytokines, including interleukin-1, TNF-α, and IL-6, impair hypothalamic–pituitary signaling, reduce peripheral hormone receptor sensitivity, and alter hormone metabolism at the tissue level. These effects are compounded by direct adrenal cytotoxicity, microcirculatory dysfunction affecting endocrine organs, and cytokine-mediated downregulation of receptor expression. In parallel, mitochondrial dysfunction and metabolic reprogramming further compromise the energetically demanding processes of hormone synthesis and intracellular signal transduction, reinforcing endocrine failure.

Clinically, sepsis is associated with a characteristic pattern of endocrine derangements. Relative vasopressin deficiency contributes to vasodilatory shock and underpins the use of vasopressin in norepinephrine-refractory states. The early stage of sepsis includes the mass-release of hypophyseal reserves of vasopressin, leading to this deficiency. The nonthyroidal illness syndrome—also referred to as sick euthyroid syndrome—reflects impaired peripheral thyroid hormone metabolism and is consistently associated with worse outcomes, although its adaptive versus maladaptive nature remains unresolved. Impaired adrenal responsiveness despite elevated adrenocorticotropic hormone levels defines critical illness-related corticosteroid insufficiency, providing the rationale for adjunctive corticosteroid therapy in refractory shock, although the use of corticosteroids in sepsis is still a controversy in critical care medicine. Insulin resistance and stress-induced hyperglycemia, beyond their metabolic consequences, directly impair innate immune function—including neutrophil activity and complement efficiency—thereby linking neuroendocrine dysfunction to the immunosuppressive phenotype observed in sepsis.

Collectively, these alterations represent a maladaptive neuroendocrine response that amplifies hemodynamic instability, perpetuates metabolic dysfunction, and impairs recovery, directly and indirectly affecting the immune system. Importantly, several components of this axis are therapeutically actionable, positioning the neuroendocrine system as both a mediator of disease severity and a potential target for precision-based interventions.