This review presents an updated and expanded synthesis of selected content from three previously published textbook chapters [1–3]. It integrates new insights into the evolutionary origins of the glucocorticoid (GC) receptor (GR) and its central role in the pathobiology of critical illness. By exploring GR alpha’s (GRα’s) multifaceted functions, the review emphasizes its profound influence throughout each disease progression and resolution phase. Key sections have been meticulously revised to provide a more comprehensive and detailed summary of our current understanding, reflecting recent advances in the field. This updated perspective aims to deepen the appreciation of GRα’s regulatory impact, from its foundational evolutionary role to its critical importance in managing homeostasis during illness. The GC signaling system, mediated by the GR, has played an essential role in vertebrate evolution and survival, facilitating precise adaptations to environmental stressors, regulating metabolism, and maintaining immune homeostasis. Despite its ancient origins, the full significance of this system began to emerge only in the early 20th century, following the discovery of cortisol’s therapeutic efficacy in treating inflammatory diseases [4]. This breakthrough represented a pivotal advancement in medicine. However, the prevailing focus on GCs as anti-inflammatory agents has often overshadowed their broader and more complex biological roles, which extend well beyond inflammation control and are fundamental to systemic adaptation.

Before exploring the complex role of the GC-GR system in orchestrating homeostatic corrections during critical illness, this review will first consider its evolutionary history and foundational significance in the development of vertebrates, including humans. This historical perspective provides essential context for understanding how the GC-GR system has evolved to meet the challenges of critical illness and restore balance during severe physiological stress.

The development of homeostatic correction mechanisms, particularly those involving the GC and GR network and their interactions with molecular pathways, has been driven by organisms’ need to survive and adapt to environmental challenges [3, 5]. The GR is essential for life, as multiple GR knockout mouse models show [6]. Steroid signaling pathways, including those mediated by GCs, arose in early jawed vertebrates during the Paleozoic era (specifically around the late Ordovician—Silurian transition) around 450 million years ago as part of the gradual emergence of the hypothalamic-pituitary-adrenal (HPA) axis in vertebrates [7]. The modern GR is the product of hundreds of millions of years of evolutionary history involving ancestral nuclear receptors, gene duplications, natural selection acting on subtle changes in receptor-ligand interactions, and the integration of dietary vitamins (vitamins C, D, and thiamine) [2] into more specialized endocrine pathways.

Interestingly, the GR, nuclear factor-kappa B (NF-κB), and the mechanisms of hemostasis and inflammation also have deep evolutionary roots, tracing their origins to lineages predating the Cambrian explosion. These early signaling systems allowed vertebrates to regulate metabolism and respond to environmental stressors, both essential for survival (Table 1) [5, 8–11]. The co-evolution of the GR with the immune system has improved its capacity to control inflammation and maintain hemostasis, ensuring a vital balance between immune defense and tissue protection. This regulatory equilibrium is illustrated by the interaction between GR and pro-inflammatory transcription factors (TFs) such as NF-κB and activator protein 1 (AP-1) [11]. Over time, the GC-GR system has evolved to respond to a wide range of stressors, including infections, injuries, psychological stress, and metabolic demands.

This evolutionary narrative is further enriched by the integral role of mitochondria, which originated from ancestral bacteria through symbiotic relationships during the same evolutionary period and became essential to the cellular energy strategies underpinning GR-mediated stress responses. The co-evolution of GR and mitochondria highlights their critical collaborative roles in enhancing cellular bioenergetics and systemic homeostasis under stress conditions, a testament to the intricacies of physiological adaptations across millions of years [3, 9]. GRα regulates mitochondria, as GRs are present within them, and glucocorticoid response elements (GREs) have been identified in the mitochondrial genome [2, 12]. During evolution, organisms began tapping into environmental sources of vitamins and minerals for essential biochemical reactions, such as energy production and enzyme function. As certain proteins acquired the ability to bind and utilize these cofactors, they became more efficient and adaptable, providing a selective advantage. Over countless generations, these cofactors became vital components of hormone synthesis and signaling pathways, ultimately shaping modern endocrine systems.

Despite this extensive evolutionary history, the body’s stress response was not systematically studied until the 20th century. This led to groundbreaking insights into systemic inflammation and its progression to organ failure [13].

The discovery of cortisone in the late 1940s, particularly for its potent anti-inflammatory effects in treating rheumatoid arthritis, marked a revolution in medicine [14]. Notably, while the risks of administering GC treatment without proper tapering were recognized early on, this crucial consideration remains overlooked in many randomized trials [2]. Since then, GC treatment has been essential in managing multifactorial inflammation; however, its biological significance extends well beyond anti-inflammatory effects. Identifying the GRα in the late 1960s and early 1970s significantly advanced our understanding of GC mechanisms. By the 1980s and 1990s, it became evident that the GC-GRα complex is crucial for transcriptional regulation, underscoring the broader influence of GCs on cellular functions [15]. For further historical context, readers are encouraged to review a comprehensive history of corticosteroid treatment in critically ill patients, which details how scientific advances have shaped treatment protocols [16]. A recent review focuses on the 75-year journey with GCs and the growing understanding of GRs [17].

Over the past two decades, the GR, particularly the GC-GRα system, has emerged as a key regulator of homeostasis by integrating and coordinating signals across multiple pathways. These pathways include stress response, inflammation, hemostasis, immune regulation, cellular bioenergetics, metabolic adaptation, circadian rhythm regulation, neural signaling, mitochondrial function, and tissue repair and regeneration. Through this intricate integration, the GR fine-tunes physiological adjustments during both health and disease progression and resolution, aiding the body in maintaining stability under physiological and pathological conditions [18, 19]. This evolving perspective challenges the traditional view of the GC-GRα system as merely anti-inflammatory, emphasizing its essential role in broader homeostatic corrections—especially in critical illness, where its diverse and extensive actions are frequently underappreciated.

The regulatory functions of GRα have evolved to optimize survival and reproduction, making the GRα system indispensable for vertebrate evolution and essential in both male and female physiology. GRα plays a crucial role in fertility [20], establishes the cellular environment necessary for normal uterine biology, and regulates placental development through uterine-specific actions. It is also vital for all fetal organs’ structural and functional maturation [21–23], influencing the expression of nearly 4,000 genes [24]. The profound importance of the GRα system in reproductive health and developmental processes ensures survival and proper function throughout life. Beyond its foundational role in initiating life, GRα maintains physiological homeostasis, supports organ function, and enables the body to respond to stress and sustain health. The GC-GRα signaling pathway influences nearly every physiological system and upholds vascular and neural integrity. It regulates the function of all organs (Table 2) and circulating cells (Table 3), covering both immune and non-immune cell types. By orchestrating coordinated and precise responses to stress, GRα is crucial for preventing or resolving multi-organ failure in critical illness [1, 19, 25].

The interaction between GRα and pro-inflammatory TFs, such as NF-κB and AP-1, is central to the stress response. Traditionally, pro-inflammatory and anti-inflammatory actions have been viewed as opposing forces in a “tug of war”. However, emerging evidence reveals a more nuanced relationship characterized by complementary co-regulation—dualism—between GRα and the NF-κB and AP-1 pathways throughout every phase of the disease process [26]. Rather than simply opposing each other, GRα and these pro-inflammatory TFs operate in a co-regulatory manner, dynamically adjusting gene expression according to the specific cellular context and inflammatory state (see below).

Building on the complex crosstalk between GRα and pro-inflammatory TFs, four seminal studies have uncovered a novel dual-phase modulation of chromatin accessibility by GRα and pro-inflammatory TFs [27–30]. In the initial phase of the host response (see below), GRα actively interacts with NF-κB or AP-1 to drive the transcription of pro-inflammatory genes, ensuring a strong immune response to external threats [27–29]. As homeostatic corrections advance, these interactions allow GRα to shift its role, aiding tissue recovery by promoting the transcription of anti-inflammatory genes [30]. During this phase, GRα modulates chromatin structure, shifting from promoting inflammation to restoring balance by activating anti-inflammatory pathways. This evolutionarily refined strategy illustrates how GRα, in coordination with pro-inflammatory TFs, ensures that the immune stress response is immediate and tightly regulated. By facilitating a rapid inflammatory reaction to threats while simultaneously preparing for anti-inflammatory and tissue-repair processes, GRα significantly contributes to efficient immune regulation and recovery during stress.

The regulation of GRα involves six sequential phases (Table S1), each critical to its roles in stress response, immune modulation, and homeostatic corrections. Various factors, including hormone availability, chromatin accessibility, post-translational modifications, oxidative stress, and cellular signaling interactions, influence these phases [18]. Each phase is supported by specific micronutrients that facilitate GRα’s function and protect it from damage, ensuring effective cellular responses during stress and recovery (Table S2).

While the discovery of GCs in 1950 [14] laid the groundwork for understanding their role in stress and inflammation, Selye [13] revolutionized the field in the 1930s and 1940s by systematically investigating the body’s response to stress. Through his pioneering work, Selye introduced the concept of general adaptation syndrome (GAS), illustrating how organisms respond to various stressors—physical, emotional, or environmental—predictably and stereotypically. He proposed that the body progresses through three distinct phases in response to stress: the Alarm Phase, characterized by the activation of immediate defense mechanisms; the Resistance Phase, in which the body adapts to the ongoing stressor; and the Exhaustion Phase, when the body’s resources become depleted. His research demonstrated that animals subjected to prolonged, multifactorial stress exhibited consistent physical changes, most notably adrenal cortex enlargement—an adaptation to increase GC production.

Selye later established that the failure of the HPA axis—the critical neuroendocrine system responsible for regulating the stress response—was pivotal in the body’s inability to cope with chronic or overwhelming stress. During the Exhaustion phase, the adrenal cortex’s capacity to produce cortisol becomes compromised, leading to the breakdown of homeostatic control, multi-system dysfunction, and immune dysregulation. This marks a shift from adaptive to maladaptive responses, characterized by dysregulated systemic inflammation and progression toward organ failure [13]. Given this understanding, therapeutic interventions such as intramuscular ACTH (adrenocorticotropic hormone) were explored [16] before the introduction of corticosteroids, aiming to stimulate cortisol production and mitigate immune dysregulation in patients with sepsis.

In critical illness, which represents the most extreme manifestation of the GAS, homeostatic corrections are essential for survival and require significant bioenergetic and metabolic resources. By the time patients reach life-support stages—such as needing vasopressors or mechanical ventilation—they are often nearing, or have reached, a state of complete exhaustion in their neuroendocrine compensatory mechanisms, cellular bioenergetic and metabolic reserves, and vital micronutrient stores [2]. This profound depletion greatly impairs GRα’s ability to effectively carry out the Priming Phase, similar to Selye’s Alarm Phase. This impairment diminishes GRα’s regulatory control over immune responses, reduces its support for essential organ functions, compromises anti-inflammatory mechanisms, and obstructs tissue repair—leading to a maladaptive response. Consequently, the body’s cumulative physiological burden, termed allostatic load [31], hinders recovery potential and significantly increases the risk of acute and long-term morbidity and mortality [1].

Understanding the evolutionary development of homeostatic correction mechanisms establishes the groundwork for appreciating the complex pathobiology underlying critical illness (Table 1). The GC-GRα system orchestrates targeted adjustments throughout critical illness, dynamically integrating signals from other hormonal and molecular pathways to maintain balance [1, 18, 32]. This adaptive capability allows the body’s responses to be precisely tailored to the specific context and target cells, enabling finely tuned adjustments that meet the unique demands of various tissues under both physiological and pathological conditions.

Central to recovery, the GC-GRα system regulates several key processes: immune modulation, which includes the regulation of inflammatory responses and immune cell activity; maintaining vascular and neural integrity through endothelial preservation and neurotransmitter modulation; energy control via mitochondrial function; the stress response and metabolism, which affect glucose and lipid homeostasis; balancing electrolytes through renal and mineralocorticoid interactions; and facilitating tissue repair through chromatin remodeling and cellular regeneration [1].

Vitamins and micronutrients play a crucial role in every phase of homeostatic corrections [2]. They are essential cofactors in metabolic processes, support GRα regulation (see supplementary information), enhance antioxidant defenses, and facilitate cellular repair. These functions are vital for maintaining physiological balance during stress and recovery. Increased metabolic demands and oxidative stress can quickly deplete these nutrients during severe illness. Throughout evolution, organisms have adapted to utilize these nutrients to boost mitochondrial energy production, regulate gene expression, and modulate immune responses. However, timely replenishment is essential to maintain resilience and promote recovery in the case of severe disease.

A previous publication initially outlined three major phases of homeostatic corrections in critical illness [33]. This review significantly updates that model (Figure 1). In an adaptive response, these phases progress successfully, leading to disease resolution and restoring homeostasis. In contrast, a maladaptive response prevents the completion of these phases, hindering recovery, perpetuating dysfunction, and potentially resulting in chronic disease or mortality.

The GC-GRα regulatory network, developed over 450 million years, is essential for maintaining and restoring homeostasis, especially during critical illness. Its ability to precisely modulate immune responses, protect vital tissues, and promote cellular recovery underscores its essential role in immediate defense and long-term healing. The GC-GR system has been uniquely adapted to meet the complex demands of homeostasis under the stress of critical illness, highlighting the importance of supporting its function as a therapeutic priority. Recent reviews have further emphasized other significant factors influencing the response to GC therapy [3, 31].

Additionally, the effectiveness of the GC-GRα complex relies closely on essential micronutrients, which are often significantly depleted in critically ill patients. This highlights the urgent need to reassess current treatment strategies to include nutrient replenishment, thereby maximizing the efficacy of GC interventions. Refer to the latest European Society for Clinical Nutrition and Metabolism guidelines for micronutrient supplementation in critically ill patients [87]. Adjusting GR activity during the phases of homeostatic corrections is crucial for developing innovative therapeutic approaches aimed at mitigating pathological pathways and restoring homeostasis. Integrating a deeper understanding of the GC-GRα network into clinical practice can transform therapeutic strategies, paving the way for improved outcomes and restoring homeostasis for critically ill patients.