Chronic Prostaglandin E2 Upregulation: A Unifying Hypothesis for Long/Post-COVID Syndrome and related syndromes

Vjera Ramer¹, Gert A. van Montfrans²

¹ Independent Researcher, Amsterdam, Corresponding Author (the.PGE2hypothesis@proton.me)
² Department of Internal Medicine, Academic Medical Center, University of Amsterdam

This article is an adaptation of the English-language publication “Persistent Prostaglandin E2 Upregulation and Hormonal Multi-Resistance: A Hypothesis for Long COVID” (Biochemistry and Biophysics Reports, 2026), in which additional background information and references can be found.¹

Contents

1. Introduction
2. PGE2 promotes other Long COVID mechanisms
3. PGE2 and its receptors
4. Susceptibility to COVID-19 and/or Long COVID
5. Signaling molecules: Elevated but functionally impaired by PGE2 upregulation?

• 1 Are subclinical cytokine storms active in Long COVID?

1. EP-receptor imbalance as a driver of chronic homeostatic dysregulation
2. The hypothesis of Hormonal Multi-Resistance
3. PGE2-mediated antagonism of other signaling molecules
4. Long COVID subphenotypes
5. Clinical implications of the hypothesis

• 10.1 PGE2 downregulation may exacerbate EP receptor imbalance
• 10.2 New perspectives on NSAID adverse effects

1. Long COVID therapies under investigation

• 11.1 Hyperbaric Oxygen Therapy (HBOT)
• 11.2 Sonlicromanol
• 11.3 Overview of Long COVID clinical trials

1. Conclusion

Appendix 1. Hypothetical Models of Resistance to AVP, Insulin, Leptin, FGF23, and IFN-γ
Appendix 2. Potential Strategies to Modulate PGE2 and EP Receptor Activity

 

1. Introduction

Prostaglandin E2 (PGE2) is a potent paracrine mediator capable of driving both acute and chronic inflammatory responses.²⁻⁴ Viral infections, including COVID-19,⁵ increase PGE2 levels, which in turn contribute to many of the characteristic manifestations of illness, including fatigue, fever, inflammation, nausea, and pain.⁶ In addition, PGE2 modulates autonomic nervous system activity, endocrine signaling, glucose metabolism, blood pressure regulation, autoantibody production, and mitochondrial function.

PGE2 signals through four receptors (EP1–EP4) and can exert diverse, often opposing physiological effects depending on the balance among these signaling pathways. Through the EP3 receptor, PGE2 promotes the production of pro-inflammatory cytokines, whereas EP4 signaling generally supports anti-inflammatory cytokine responses. However, under conditions of chronically elevated PGE2, EP4 signaling—which can proceed through multiple intracellular pathways—may become pro-inflammatory (see Section 3).

PGE2 has been shown to inhibit numerous hormones and signaling molecules that themselves stimulate COX-2 expression and PGE2 synthesis. This also appears to apply to several mediators that are consistently reported to be elevated and/or dysfunctional in patients with Long COVID (see Section 5). We hypothesize that persistently high PGE2 levels may result in excessive inhibition (“PGE2 dominance”), leading to self-reinforcing feedback loops that produce functional resistance to these signaling molecules.

As a consequence, these and other PGE2-stimulating hormones may remain elevated while becoming functionally ineffective, thereby sustaining PGE2 dominance and perpetuating inflammatory processes.

The available literature suggests that dysregulation of PGE2 and EP receptor signaling is consistent with the remarkably diverse symptomatology of Long COVID¹. Elevated levels of PGE2, as well as related prostaglandins⁸ have been reported in several Long COVID studies⁹˒¹⁰. We therefore propose that chronic PGE2 upregulation may play a central role in the pathogenesis of Long COVID. Validation of this hypothesis appears feasible through the assessment of EP receptor expression profiles¹ and may provide a foundation for novel therapeutic approaches.

2. PGE2 Promotes Other Proposed Mechanisms of Long COVID

Multiple pathophysiological mechanisms have been proposed to underlie Long COVID, including viral persistence, autoimmunity, mitochondrial dysfunction, and autonomic dysregulation. To date, however, no clear molecular mechanism has been identified that links the initial infection to the persistence of symptoms. A unifying and testable framework capable of explaining the broad clinical heterogeneity of Long COVID remains lacking.

Based on an extensive review of the literature, we identify prostaglandin E2 (PGE2) as a potential upstream regulator that may integrate and drive several of these mechanisms.

Numerous Long COVID-related mechanisms described in the literature¹¹˒¹² are directly linked to PGE2 activity. PGE2 upregulation has been reported to promote:

• Viral persistence and viral reactivation¹³
• Production of pro-inflammatory cytokines that further stimulate PGE2 synthesis (cytokine storms) ¹⁴⁻¹⁶
• Autoantibody production, autoantibody class switching¹⁷⁻¹⁹ and autoimmunity²⁰˒²¹
• Thrombotic complications through EP3 signaling²² and COX-2/TXA2-mediated pathways²³˒²⁴
• Microbiome disruption²⁵⁻²⁷ and bacterial translocation²⁸
• Mitochondrial dysfunction²⁹⁻³¹
• Endothelial dysfunction³²˒³³
• Suppression of serotonin synthesis and secretion³⁴˒³⁵
• Dysregulation of the autonomic nervous system³⁶⁻³⁸

Taken together, these observations suggest that PGE2 may occupy an upstream position in the network of biological processes implicated in Long COVID.

3. PGE2 and Its Receptors

The first step in PGE2 biosynthesis involves calcium (Ca²⁺)-dependent activation of cytosolic phospholipase A2 (PLA2), which releases arachidonic acid (AA) from membrane phospholipids³⁹. Under physiological conditions, PGE2 synthesis proceeds primarily through cyclooxygenase-1 (COX-1), which is constitutively expressed in most tissues. Under conditions of physical or psychological stress, however, cyclooxygenase-2 (COX-2) is induced. The final step in PGE2 synthesis is catalyzed by microsomal prostaglandin E synthases (mPGES), most commonly mPGES-1.

PGE2 acts through four receptors (EP1–EP4), whose expression varies among tissues and individuals. EP1 is expressed predominantly in the brain and nervous system, EP2 is found mainly in organs and connective tissues, whereas EP3 and EP4 are broadly distributed⁴⁰. EP receptors have also been identified in mitochondrial membranes⁴¹ and nuclear membranes⁴² suggesting an evolutionarily ancient and fundamental biological role.

Throughout this article, the term “EP3” refers to PGE2 signaling mediated through the EP3 receptor.

The physiological effects of PGE2 receptor activation are highly context-dependent and frequently opposing. Much of this diversity is attributable to their effects on the key intracellular second messengers cyclic adenosine monophosphate (cAMP) and calcium (Ca²⁺). Activation of EP1 (which increases intracellular Ca²⁺) and EP3 (which increases Ca²⁺ while reducing cAMP) generally promotes pro-inflammatory and sympathetic responses, including fever and elevated blood pressure. In contrast, activation of EP2 and EP4 (which increase cAMP) typically produces anti-inflammatory and parasympathetic effects, such as reduced body temperature and lower blood pressure.

PGE2 suppresses parasympathetic signaling through EP3 while simultaneously enhancing sympathetic signaling through the same receptor. This may help explain how a paracrine mediator, which by definition acts locally within or near tissues, can nevertheless exert broad systemic effects.

We hypothesize that differences in the balance between EP3 and EP4 receptor expression contribute to interindividual variation in responses to infection. Relatively high EP3 activity (“EP3-up”) may be associated with more severe acute disease manifestations, including high fever and acute pneumonia, whereas relatively high EP4 activity (“EP3-down”) may be associated with milder acute disease⁴³ but potentially a greater risk of developing Long COVID.

4. Susceptibility to COVID-19 and/or Long COVID

Elevated PGE2 concentrations have been documented in patients with COVID-19. Factors such as advanced age, increased body mass index, male sex, and comorbidities are associated with higher baseline PGE2 levels and are likewise linked to more severe disease outcomes⁴⁴. This association may reflect increased expression of the pro-inflammatory EP3 receptor (“EP3-up”).

Notably, however, many patients who subsequently develop Long COVID experienced only mild acute infection. We therefore propose that a receptor profile characterized by EP4 predominance, resulting in reduced functional EP3 signaling (“EP3-down”), may also predispose individuals to Long COVID.

As discussed above, chronically elevated PGE2 levels may shift normally anti-inflammatory EP4 signaling toward pro-inflammatory pathways. Through distinct EP receptor-mediated signaling routes, PGE2 can influence differentiation of T cells into multiple T-helper (Th) cell subsets⁴⁵. It may promote differentiation toward anti-inflammatory Th2 cells through EP2 and EP4 signaling⁴⁶˒⁴⁷. but also toward pro-inflammatory Th1 cells through EP1⁴⁸ and EP4 signaling⁴⁸˒⁴⁹, as well as toward Th17 cells through EP2/EP4 pathways⁴⁹⁻⁵².

The receptors shown in bold in the original literature are those believed to exert the greatest influence on these differentiation processes.

Enhanced Th17 activity may promote the production of pathogenic IgG autoantibodies, which have been reported both in Long COVID patients and in experimental SARS-CoV-2 infection models. Such autoantibodies are known to interfere with receptor signaling and may therefore contribute to hormonal resistance and the persistence of inflammatory processes.

5. 
   Signaling Molecules Elevated but Functionally Impaired by PGE2 Upregulation?

Several signaling molecules—and their associated physiological pathways—have been reported to be elevated or dysregulated in patients with acute and Long COVID. These include arginine vasopressin (AVP) and thirst regulation, leptin and lipid metabolism, insulin resistance and glucose homeostasis, fibroblast growth factor 23 (FGF23) and phosphate regulation, and interferon-γ (IFN-γ) and hyperinflammation.

We propose that these observations may be explained, at least in part, by chronic feedback antagonism mediated by PGE2, since each of these signaling molecules can stimulate PGE2 production. Examples are summarized in Table 1.

Table 1. Examples of PGE2-stimulating signaling molecules that may be functionally inhibited by PGE2

Elevated/dysregulated in (acute and) Long COVID	PGE2 is stimulated by these mediators	PGE2 may antagonize these mediators	Resistance to these mediators has been observed in other contexts
AVP1 Dorst2	AVP3	AVP4	AVP5
Leptine6  Dislipidemia6	Leptine7	Leptine8	Leptine9
Insuline-resistentie10 Glucose6	Glucose11	Insuline8	Insuline12
FGF2313,14 Fosfaat15	FGF2316,17	FGF2318	FGF2319,20
IFN-γ 21,22 hyperinflammatie23	IFN-γ 24,25	IFN-γ 26	IFN-γ27
For more infornmation see: Appendix 1. Hypothetical Models of Resistance to AVP, Insulin, Leptin, FGF23, and IFN-γ

 

5.1. Subclinical Cytokine Storms in Long COVID?

Elevated cytokine levels have been reported in Long COVID. Across multiple studies, the following inflammatory mediators have been proposed as biochemical biomarkers for Long COVID subtypes: tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and interleukin-17 (IL-17).

Notably, all of these cytokines are reported to be stimulated by prostaglandin E2 (PGE2) via different EP receptor pathways. Conversely, these cytokines may also promote PGE2 production and/or EP receptor expression, suggesting the existence of bidirectional positive feedback loops (see Table 2).

 

Table 2. Cytokines Proposed as Biomarkers in Long COVID

 

Elevated in Long COVID subphenotypes	This mediator stimulates	This mediator is stimulated by PGE2:
il-1β22,28	PGE2/COX-2 en EP1- en ‘EP4’-expressie29,30,31,25,32	via EP129,33-35 en EP436
Il-637	PGE2/COX-238	via EP139, EP240,39,41, EP342-44 en EP445,46,38
Il-1747, 22,48	PGE2/COX-232	via EP2/’EP4’49
TNF-alpha37,28	PGE2/COX-225,32	geremd via EP2/EP441,50

 

We propose that cytokines and other signaling molecules that are stimulated by PGE2, may be elevated through two non-exclusive mechanisms: either due to a) direct stimulation of their production by PGE2, or b) via homeostatic upregulation within a resistance loop, in which their signaling is antagonized by PGE2 while they continue to promote PGE2 synthesis.

PGE2 upregulation itself has also been identified as a biomarker in Long COVID⁹˒¹⁰. In a 2025 study, PGE2 was ranked among the top three most important biomarkers, together with C-reactive protein (CRP). In another study, CRP was identified as the only common denominator across all Long COVID subphenotypes⁸⁹. CRP is stimulated by interleukin-6 (IL-6)⁸⁹. Il-6 is a key inflammatory cytokine that itself can be induced through multiple PGE2-dependent pathways (see Table 2).

PGE2 upregulation may also directly amplify its own synthesis, as elevated PGE2 levels promote the expression of upstream enzymes and substrates involved in its biosynthesis:

• COX-2 via EP2/EP4–cAMP signaling pathways²³
• PLA2/arachidonic acid via EP1/Ca²⁺ signaling¹⁰¹
• mPGES-1 via IL-1β–dependent upregulation¹⁰²

Together, these interconnected pathways suggest that PGE2-centered signaling networks may contribute to persistent inflammation and chronic symptomatology.

 

6. EP Receptor Imbalance as a Driver of Chronic Homeostatic Dysregulation

PGE2 is not only elevated during infection but is also induced by a wide range of physical and psychological stressors, including tissue injury, fractures, and dehydration. During illness, reduced activity and behavioral adaptation may prioritize energy allocation toward resolving the underlying stressor (e.g., viral clearance or tissue repair).

PGE2 appears to function as a systemic “troubleshooter” regulating key homeostatic processes such as blood pressure, glucose metabolism, and osmolality. Under physiological conditions, PGE2 upregulation generally contributes to the restoration of homeostasis by modulating hormonal systems that increase or decrease relevant physiological set points. However, when EP-signaling is imbalanced, elevated PGE2 levels may themselves contribute to maladaptive regulation.

We hypothesize that both EP3-up and EP3-down states, and excess or lack of the other EP receptors, may result in chronically elevated PGE2 levels. Persistent homeostatic dysregulation may generate continuous stress signals, which in turn sustain PGE2 production (see Appendix 1 for additional details and references).

 

7. Hypothesis of Hormonal Multi-Resistance

We introduce the concept of hormonal multi-resistance as a mechanism underlying persistent PGE2 upregulation.

We observed that many hormones inhibited by PGE2 also act as upstream stimulators of PGE2 production. This may represent a physiological feedback mechanism that limits their activity under normal conditions or helps modulating the immune system. However, in the presence of sustained high PGE2 levels (“PGE2 dominance”), these signaling molecules may become functionally suppressed.

This antagonism may lead to a state of persistent resistance to PGE2-stimulating hormones, as these mediators continue to drive PGE2 production while their own signaling is progressively impaired.

From an evolutionary perspective, this mechanism may have been adaptive, for example by conserving energy during illness or periods of resource scarcity. Comparable forms of hormonal resistance have been described in hibernating animals. We hypothesize that this evolutionarily conserved survival mechanism may become dysregulated in humans and acquire pathological properties.

 

8. PGE2-Mediated Antagonism of Other Signaling Molecules
   
   

PGE2 may inhibit hormones and signaling molecules through several distinct mechanisms:

1. Autoantibodies (via EP2 / EP4 signaling)

PGE2 promotes the production and class switching of autoantibodies (IgM → IgG/IgE).¹⁸˒¹⁰³˒¹⁰⁴ IgG autoantibodies targeting receptors such as angiotensin II and acetylcholine receptors have been reported in Long COVID patients¹⁰⁵˒¹⁰⁶. These autoantibodies may interfere with receptor binding and, according to our hypothesis, may contribute to functional resistance phenomena.

2. Receptor phosphorylation (via EP1)

PGE2 may promote receptor phosphorylation, thereby reducing ligand binding affinity and potentially enhancing autoantibody binding.

3. Inhibition of secretion (via EP3 signaling)

Through EP3 signaling, PGE2 may suppress the release of mediators such as acetylcholine, insulin, and monoamines, potentially contributing to functional resistance states.

4. Shared intracellular signaling pathways (via EP1–EP4)

PGE2 may interfere with G protein-coupled receptor (GPCR) signaling through competition for shared intracellular pathways, including cAMP and Ca²⁺ signaling. This interaction may also operate bidirectionally and may help explain the reported anti-inflammatory effects of monoamines, which at sufficiently high concentrations may antagonize PGE2 signaling.

 

9. Long COVID Subphenotypes
   
   

Variation in EP receptor expression may contribute to distinct clinical subtypes of Long COVID. Under conditions of persistently elevated PGE2 levels, differences in receptor balance may result in heterogeneous symptom profiles. Multiple studies have consistently identified two to four subphenotypes with overlapping biomarker signatures. We relate these to EP receptor expression profiles (see Table 3).

In a dataset of approximately 20,000 patients (with a control group of 13,000), Zhang et al. (2023) identified four subtypes (Types 1–4). We observed that Type 1 corresponds to our proposed EP3-up category, whereas Types 2–4 correspond to three subgroups within the EP3-down category, characterized by predominant expression of EP1, EP4, and EP2, respectively.

In the supplementary material of Sidiropoulou et al., four subtypes (Types A–D) are described, which in the main publication were consolidated into two broader phenotypes (“respiratory” and “non-respiratory”). These four subtypes (A–D) show close correspondence with those described by Zhang et al. (see Table 3). In this study, the “Respiratory” cohort was associated with upregulation of interleukin-1 (IL-1) family cytokines as biomarkers, which is consistent with our proposed profiles, as IL-1β correlates with EP1 and/or EP4 upregulation. These receptors are implicated in T helper cell differentiation toward Th1 responses, which in turn promote IL-1β signaling, while IL-1β may further enhance EP1 and EP4 expression (see Table 2, Section 5.1).

 

Table 3. Long COVID Subphenotypes

(For references, see Appendix MMC.3 in Appendix A of the original article¹)

 

LC-Studies	Phenotypic Categories and Associated Biomarkers
	Category A: “EP3-up” More frequently male More frequently hospitalized	Categorie B: ‘EP3-down’   More frequently female More often a mild disease course, but in some cases also severe disease*
Danesh et al. (2023)¹⁰⁷ (symptom-based analysis) “Pulmonary cluster” (acute pneumonia) “Neuropsychiatric cluster”	‘Pulmonary cluster’ (acute longontsteking)	‘Neuropsychiatric cluster’
Kervevan et al. (2023) ¹⁰⁸ (symptom-based analysis and clinical investigation)	“Seropositive Long COVID” Higher levels of antibodies against SARS-CoV-2	“Seronegative Long COVID” Lower levels of antibodies against SARS-CoV-2
Zhang51	Type 1 ‘Cardiac and renal’	Type 2 ‘Respiratory sleep and anxiety’	Type 3 ‘Muskuloskeletal and neuropsychiatric’	Type 4 ‘Gastro-intestinal and Respiratory’   Less burden of symptoms
Sidiropoulou (2025)22 (symptoom-analyse en klinisch onderzoek in een overwegend gehospitaliseerd geweest  cohort)	Type A ‘Fatigue’	Type B ‘Respiratory’           Cytokine interleukin-1 (il-1)	Type D ‘Fatigue’ Muskuloskeletal	Type C ‘Respiratory’ Less burden of symptoms compared to type D   il-1
The hypothetical EP-profiles below correspond with all abovementioned biomarkers
Ramer en van Montfrans (2026)52	‘EP3-up-down’*   (After severe infection EP3 may be downregulated)	‘EP3-down’ ‘EP1-up’	‘EP3-down’ ‘EP2-up’	‘EP3-up-down’* ‘EP4-up’
* Extreme upregulation of PGE2 may shift “EP3-up” expression toward an “EP3-down” phenotype.
Unreviewed hypothesis on potentially corresponding immune responses:
Hypothetical immune response	TNF-alpha50	Th153	Th1754	Th255
		Il-1β IFN-γ	Il-17	Il-1β Il-4

 

10. Clinical Implications of the Hypothesis
    
    

Previous studies have shown that PGE2 and related prostaglandins remain elevated in patients with Long COVID⁸⁻¹⁰ This may be explained by the hypothesis of persistent PGE2 upregulation in interaction with PGE2-stimulating signaling molecules.

We hypothesize that, similar to certain endocrine hormones, some cytokines may remain upregulated via different pathways in different patient subgroups—either through an EP3-up or an EP3-down mechanism. Interleukin-6 (IL-6) may serve as an example.

This interpretation is supported by clinical observations from acute COVID-19, where anti–IL-6 therapies showed benefit in severely dyspneic patients but not in hospitalized, non-ventilated patients⁷⁵ According to our model, this may be explained as follows: in an EP3-up/EP4-down phenotype, more severe pulmonary inflammation would be expected than in an EP3-up/EP4-up phenotype.

If IL-6 is upregulated in the latter group through an EP4-mediated resistance loop, anti–IL-6 therapy may be ineffective because it does not interrupt the underlying resistance network (i.e., PGE2 continues to dominate IL-6 signaling).

For the development of effective Long COVID therapies, it is therefore essential to determine which EP receptors are dominant in individual patients. This raises a central clinical question: do both EP3-up and EP3-down patients benefit from direct systemic reduction of PGE2 itself?

 

10.1. PGE2 Downregulation May Exacerbate EP Receptor Imbalance

The following consideration is of major importance for therapeutic implications: systemic reduction of PGE2 may alter EP receptor balance.

PGE2 upregulation is associated with reduced EP3 expression and often increased expression of EP1, EP2, and EP4 receptors.¹⁰⁹⁻¹¹¹ Conversely, PGE2 downregulation is presumed to result in increased EP3 expression and reduced expression of EP1, EP2, and EP4.

While this shift may be beneficial in EP3-down patients, it may be detrimental in EP3-up patients, as further increases in EP3 expression could exacerbate the underlying receptor imbalance.

 

10.2. New Insights into NSAID Adverse Effects

Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce PGE2 levels through inhibition of cyclooxygenase-2 (COX-2), an enzyme involved in the synthesis of PGE2 and other prostaglandins. NSAIDs are known to cause adverse effects in certain patient populations. While insufficient selectivity may contribute to these effects, we propose that a more important factor may be paradoxical changes in receptor expression and signaling balance.

The hypothesis that EP3-up patients are particularly susceptible is supported by the observation that major NSAID-related adverse effects are frequently cardiovascular and renal in nature—physiological systems in which EP3 signaling plays a key role. In contrast, EP4 signaling (which is relatively reduced in the EP3-up phenotype) exerts protective effects against gastric ulceration.¹¹² This is consistent with the well-known gastrointestinal complications of NSAID use, which may therefore be more likely in EP3-up patients.

 

11. Long COVID Therapies Under Investigation Reduce PGE2 Activity
    
    

All therapies investigated for Long COVID to date, insofar as can be determined from the literature, appear to exert either direct or indirect inhibitory effects on PGE2 activity. The two interventions that most clearly reduce systemic PGE2 levels are hyperbaric oxygen therapy (HBOT) and sonlicromanol.

 

11.1. Hyperbaric Oxygen Therapy

Hyperbaric oxygen therapy (HBOT) reduces PGE2 activity, at least in part, through inhibition of COX-2 (similar to NSAIDs). Clinical studies have reported mixed outcomes, with some patients showing improvement, while others show no response or clinical deterioration.

These heterogeneous results may be explained by differences in EP receptor profiles. HBOT may be indicated for Type 3 (EP3-down/EP4-up) patients and potentially contraindicated in Type 1 (EP3-up/EP4-down) patients.

In the context of systemic PGE2 downregulation, an increase in EP3 expression and a decrease in EP4 expression would be expected—opposite to the pattern observed in states of strong or sustained PGE2 upregulation. Consequently, HBOT may either normalize or exacerbate EP receptor imbalance, thereby influencing whether homeostatic dysregulation and PGE2-driven inflammation persist or resolve.

 

11.2. Sonlicromanol

Sonlicromanol inhibits microsomal prostaglandin E synthase-1 (mPGES-1) and therefore acts more selectively than COX-2–targeting NSAIDs. This makes it a promising candidate for EP3-down patients and potentially—at lower doses or in combination with appropriate EP receptor agonists or antagonists¹¹³—also for EP3-up patients.

 

11.3. Overview of Long COVID Treatments

 

See the original artikcle for references

“Table 4. (Partially) successful long COVID interventions; PGE2 hypothesis-driven

mechanistic explanations”⁵²

Table 4. Overview of Investigated Long COVID Treatments (non-exhaustive)

 

Additional Therapeutic Approaches

For further treatment options derived from or supported by our hypothesis, see Appendix 2: “Potential Strategies to Modulate PGE2 and EP Receptor Activity”. These include, among others: bupropion, DNA demethylation using 5-aza-dC, EP receptor agonists and antagonists, immunoadsorption, methylphenidate, PGE1/PGE3 analogues, P15HDG activators, selective serotonin reuptake inhibitors (SSRIs), and transcranial stimulation techniques.

 

12. Discussion

The hypothesis that persistent PGE2 upregulation and hormonal multi-resistance play a central role in Long COVID provides a potential explanation for its heterogeneous clinical presentation, as well as for the variable efficacy of therapies that have been investigated for this condition.

This literature-based hypothesis has several limitations. First, PGE2 is part of a complex inflammatory network, and its dysregulation is closely intertwined with multiple other factors, including alterations in arachidonic acid metabolism, immune cell composition, and other eicosanoid pathways, which could not all be fully addressed in this analysis¹¹⁴˒¹¹⁵ Second, a substantial proportion of the supporting evidence is derived from biological and clinical contexts other than SARS-CoV-2 infection. Therefore, this hypothesis should be interpreted as a coherent and testable conceptual framework rather than a confirmed mechanism.

If validated, this model could support more individualized therapeutic strategies targeting PGE2 signaling and specific EP receptor pathways. The ultimate objective would be the restoration of physiological homeostasis and the disruption of self-sustaining pathological feedback loops, thereby enabling simultaneous—and potentially durable—improvement across multiple symptom domains.

 

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