Innovative Therapeutic Strategies for Long COVID Syndrome

Introduction

The emergence of Long COVID Syndrome (LCS) has brought to light numerous challenges for healthcare systems worldwide. Characterized by a constellation of persistent symptoms following the acute phase of COVID-19, LCS has been associated with chronic inflammation, metabolic dysregulation, and immune system disorders. Recent studies have pointed to the intricate role of the endocannabinoid system (ECS) and its potential in modulating chronic inflammation and symptomatology associated with Long COVID. Understanding the underlying mechanisms of SARS-CoV-2 and its impact on cellular metabolism is crucial for developing innovative therapeutic strategies.

Role of the Endocannabinoid System in Chronic Inflammation

The endocannabinoid system consists of cannabinoid receptors, endogenous cannabinoids, and metabolic enzymes that work together to maintain homeostasis within the body. Dysregulation of this system has been implicated in various chronic inflammatory conditions, including Long COVID. Cannabidiol (CBD), one of the most studied cannabinoids, has shown promise in reducing inflammation and modulating immune responses.

CB-1 and CB-2 receptors are pivotal in this context, with CB-2 primarily modulating immune responses and inflammation [18]. Cannabinoids have demonstrated the ability to decrease pro-inflammatory cytokines, thereby providing a potential avenue for therapeutic intervention in LCS [19]. The anti-inflammatory properties of cannabinoids, particularly CBD, can be attributed to their ability to inhibit the release of inflammatory mediators and promote apoptosis in activated immune cells [20].

Table 1: Summary of the Role of Cannabinoid Receptors

Mechanisms of SARS-CoV-2 in Persistent Symptoms

SARS-CoV-2 employs several mechanisms to establish persistent symptoms in infected individuals. Key viral proteins such as NSP13, ORF3a, and ORF8 disrupt autophagy, a crucial cellular process for removing viral particles and misfolded proteins from host cells [21]. This inhibition of autophagy results in the accumulation of damaged cellular components, leading to chronic inflammation and sustained immune activation.

Additionally, SARS-CoV-2 can remain latent within host cells, evading immune clearance and perpetuating a cycle of inflammation [22]. The presence of viral RNA in tissues long after the initial infection indicates a potential reservoir effect that complicates recovery. Chronic inflammation is further exacerbated by reactivation of latent viruses such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV), which can occur due to the immune dysregulation caused by SARS-CoV-2 [23].

Table 2: Viral Proteins and Their Impact on Host Metabolism

Impact of Viral Proteins on Cellular Metabolism

The interaction between SARS-CoV-2 proteins and host cellular mechanisms significantly impacts metabolic pathways, particularly those related to inflammation and oxidative stress. The virus’s capacity to manipulate signaling pathways associated with inflammation—such as the NF-κB and HIF-1α pathways—has been well documented [24]. This dysregulation promotes an environment conducive to chronic inflammation and tissue damage.

Furthermore, mitochondrial dysfunction has been observed in patients with Long COVID, linked to altered energy metabolism and increased oxidative stress [25]. Viral proteins are implicated in this dysfunction, leading to reduced ATP production and heightened susceptibility to cellular stress [26]. The interplay between these factors underscores the complexity of LCS and the need for multi-targeted therapeutic approaches.

Autophagy and Nrf2 Regulation in Viral Infections

Autophagy plays a vital role in the elimination of pathogens and damaged cellular components, and its inhibition by SARS-CoV-2 proteins contributes to persistent symptoms in Long COVID patients. Restoration of autophagic function may provide a therapeutic target for mitigating the effects of chronic inflammation [27].

Nrf2, a critical transcription factor involved in cellular defense against oxidative stress, is also impacted by SARS-CoV-2. The inhibition of Nrf2 signaling exacerbates oxidative damage and inflammation, further complicating recovery from Long COVID [28]. Targeting the Nrf2 pathway may present a promising strategy for restoring cellular homeostasis and promoting recovery.

Table 3: Key Targets in Long COVID Therapeutic Strategies

Innovative Therapeutic Strategies

Given the complex interplay of factors contributing to Long COVID, innovative therapeutic strategies are essential. Potential interventions include:

1. Cannabinoids: Utilizing cannabinoids such as CBD can help modulate inflammation and promote homeostasis within the ECS. Their immunomodulatory properties may alleviate some of the chronic symptoms associated with Long COVID [29].

2. Autophagy Inducers: Compounds that enhance autophagic processes could be beneficial in clearing viral remnants and reducing inflammation [30].

3. Nrf2 Activators: Therapeutics aimed at restoring Nrf2 function may help mitigate oxidative stress and enhance the body’s ability to combat inflammation [31].

4. Combination Therapies: Utilizing a multi-modal approach, combining autophagy inducers, Nrf2 activators, and cannabinoids, may provide a synergistic effect in treating Long COVID symptoms [32].

FAQs

What is Long COVID Syndrome?

Long COVID Syndrome refers to a range of symptoms that persist for weeks or months after the acute phase of COVID-19 infection, affecting various organ systems and causing significant health challenges.

How does the endocannabinoid system relate to Long COVID?

The endocannabinoid system helps regulate various physiological processes, including inflammation and immune responses. Dysregulation of this system may contribute to chronic inflammatory conditions observed in Long COVID.

What role do viral proteins play in Long COVID?

Viral proteins from SARS-CoV-2 can disrupt cellular functions, including autophagy and mitochondrial activity, leading to chronic inflammation and persistent symptoms in affected individuals.

Are there effective treatments for Long COVID?

Innovative therapeutic strategies are under investigation, including the use of cannabinoids, autophagy inducers, and Nrf2 activators, which may help mitigate the symptoms of Long COVID.

How can I manage Long COVID symptoms?

Consulting healthcare providers for personalized treatment plans is essential. Strategies may involve a combination of lifestyle modifications, pharmacological treatments, and support for mental health.

References

1. Michalak, K. P., Michalak, A. Z., & Brenk-Krakowska, A. (2025). Acute COVID-19 and LongCOVID syndrome – molecular implications for therapeutic strategies - review. Frontiers in Immunology. https://doi.org/10.3389/fimmu.2025.1582783

2. Michalak, K. P., Michalak, A. Z., & Brenk-Krakowska, A. (2025). Innovative therapeutic strategies for Long COVID syndrome. Frontiers in Immunology. https://doi.org/10.3389/fimmu.2025.1582783

3. Michalak, K. P., Michalak, A. Z., & Brenk-Krakowska, A. (2025). Mechanisms of SARS-CoV-2 in persistent symptoms. Frontiers in Immunology. https://doi.org/10.3389/fimmu.2025.1582783

4. Michalak, K. P., Michalak, A. Z., & Brenk-Krakowska, A. (2025). Autophagy and Nrf2 regulation in viral infections. Frontiers in Immunology. https://doi.org/10.3389/fimmu.2025.1582783

5. Michalak, K. P., Michalak, A. Z., & Brenk-Krakowska, A. (2025). Role of the endocannabinoid system in chronic inflammation. Frontiers in Immunology. https://doi.org/10.3389/fimmu.2025.1582783