Due to its rapid spread and rising mortality rate, the pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as Corona Virus Disease 2019 (COVID-19), has had a profound impact on the entire world.
As of February 2023, more than 6.8 million fatalities and over 755 million COVID-19 cases have been reported globally (Organization, 2023).
While some infected individuals exhibit only mild signs and symptoms such as fever, tiredness, and a chronic cough, a subset develops severe COVID-19 (Borges do Nascimento et al., 2020).
Patients with severe COVID-19 may experience immunological and coagulation abnormalities, as well as organ damage to the lungs, heart, kidneys, brain, liver, and other organs (Mehta et al., 2020). Additionally, individuals with varying degrees of COVID-19 severity, including those with mild to moderate symptoms, often experience neurological, respiratory, or cardiovascular symptoms that can persist for weeks or even months, commonly referred to as “post-COVID-19 syndrome” or “long COVID” (Yong, 2021).
Despite the availability of vaccines for COVID-19, the emergence of mutant strains of the virus continues to pose a threat. While antiviral small-molecule oral drugs such as Paxlovid and Molnupiravir have shown efficacy in preventing hospital stays and reducing deaths in high-risk COVID-19 patients and have been approved for treatment, they come with strict population and timing restrictions for use. Furthermore, there have been reports of recurrent infection and symptom rebound after a 5-day course of therapy with Paxlovid (Rubin, 2022).
Cell death plays a dual role in viral infections (Imre, 2020). On one hand, it can eliminate cells infected with SARS-CoV-2, thereby inhibiting virus replication and spread. On the other hand, dysregulated cell death can lead to uncontrolled cellular damage and immune responses, contributing to the multi-organ manifestations observed in COVID-19 patients during acute infection and potentially leading to long COVID. Ferroptosis, a form of cell death induced by the small molecule erastin, was first identified in 2012 (Dixon et al., 2012).
Unlike apoptosis, a type of programmed cell death, ferroptosis primarily occurs due to an accumulation of intracellular lipid reactive oxygen species (ROS), leading to lethal lipid peroxidation (Hadian and Stockwell, 2020).
This process is named ferroptosis because iron ion overload is a critical factor in lipid peroxidation. 4-Hydroxynonenal (4-HNE), a breakdown product of lipid peroxidation associated with ferroptosis, can serve as a marker for this form of cell death. The pathology report of a COVID-19 patient in 2020 showed a decreased lymphocyte count and positive staining of the proximal renal tubules and myocardial tissue, suggesting a link between ferroptosis and organ damage caused by COVID-19 (Jacobs et al., 2020).
An increasing number of studies now suggest a strong association between ferroptosis and COVID-19. This article discusses the key molecular mechanisms of ferroptosis and its correlation with multi-organ complications in COVID-19, providing insights into potential treatment strategies to mitigate the effects of COVID-19.
Signatures of Ferroptosis in COVID-19 Multi-Organ Complications
While respiratory symptoms are the most common manifestation of COVID-19, severe patients may experience pulmonary, cardiac, renal, neurological, gastrointestinal, and hepatic damage, as well as impaired immune and coagulation function (Mehta et al., 2020). Increasing evidence suggests that ferroptosis is involved in the pathogenesis of these multi-organ complications.
In the lungs, SARS-CoV-2 primarily targets the respiratory epithelial cells, leading to inflammation, oxidative stress, and tissue damage (Mason, 2020). Ferroptotic cell death has been observed in the lungs of COVID-19 patients, characterized by increased lipid peroxidation, decreased glutathione levels, and altered expression of key regulators of ferroptosis such as glutathione peroxidase 4 (GPX4) and acyl-CoA synthetase long-chain family member 4 (ACSL4) (Barnes et al., 2020; Proneth and Conrad, 2019). The activation of ferroptosis in lung tissue contributes to the progression of acute respiratory distress syndrome (ARDS), a severe complication of COVID-19 characterized by widespread inflammation and lung tissue injury (Ackermann et al., 2020).
Cardiac involvement is another significant complication observed in COVID-19 patients, even in those without pre-existing cardiovascular conditions. Ferroptosis has been implicated in COVID-19-related myocardial injury. Inflammatory cytokines and oxidative stress, induced by viral infection, contribute to cardiomyocyte damage and cardiac dysfunction (Tay et al., 2020). Studies have demonstrated increased levels of lipid peroxidation and decreased expression of GPX4 in the myocardium of COVID-19 patients, suggesting the involvement of ferroptosis in myocardial injury (Li et al., 2020).
Renal dysfunction is a common complication in severe COVID-19 cases. The kidneys are susceptible to SARS-CoV-2 infection, with the virus targeting renal tubular epithelial cells. Ferroptotic cell death has been observed in renal tissues of COVID-19 patients, accompanied by lipid peroxidation and decreased expression of GPX4 (Akhtar et al., 2020).
The dysregulation of iron metabolism and lipid peroxidation in the kidneys contributes to acute kidney injury (AKI) in COVID-19 patients (Bolisetty and Agarwal, 2019).
Neurological manifestations in COVID-19 include anosmia, ageusia, headache, dizziness, encephalopathy, stroke, and seizures. Ferroptosis has been implicated in COVID-19-related neurological complications.
The brain is vulnerable to oxidative stress and inflammation induced by SARS-CoV-2 infection (Mehta et al., 2020). Increased lipid peroxidation and altered expression of ferroptosis-related genes have been observed in the brains of COVID-19 patients, suggesting a potential role of ferroptosis in neuroinflammation and neuronal damage (Song et al., 2021).
Gastrointestinal (GI) symptoms such as diarrhea, nausea, vomiting, and abdominal pain have been reported in COVID-19 patients. The GI tract expresses high levels of angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2 entry (Hashimoto et al., 2020).
Ferroptosis has been implicated in the pathogenesis of GI complications in COVID-19, including mucosal injury and intestinal barrier dysfunction (Yang et al., 2020). Increased lipid peroxidation and decreased GPX4 expression have been observed in the intestines of COVID-19 patients.
Hepatic involvement in COVID-19 is characterized by liver dysfunction and elevated liver enzymes. The liver plays a crucial role in maintaining iron homeostasis and detoxification processes, making it susceptible to ferroptotic cell death. Studies have shown increased lipid peroxidation and altered expression of ferroptosis-related markers in the liver tissues of COVID-19 patients, indicating the potential involvement of ferroptosis in liver damage and dysfunction (Nguyen et al., 2021).
Mechanisms of Ferroptosis in COVID-19
The mechanisms underlying ferroptosis in COVID-19 are multifaceted and involve a complex interplay of viral infection, inflammation, oxidative stress, and dysregulation of iron metabolism. SARS-CoV-2 infection triggers an excessive inflammatory response, characterized by the release of pro-inflammatory cytokines and chemokines, leading to a state of systemic inflammation known as a cytokine storm (Mehta et al., 2020). This cytokine storm contributes to the production of reactive oxygen species (ROS) and lipid peroxidation, promoting ferroptotic cell death.
The dysregulation of iron metabolism is a key factor in ferroptosis. Iron ions participate in Fenton reactions, generating highly reactive hydroxyl radicals that initiate lipid peroxidation and subsequent cell death (Stockwell et al., 2017). In COVID-19, the dysregulation of iron homeostasis occurs due to several factors.
The cytokine storm and inflammation induce hepcidin release, an iron regulatory hormone, leading to increased iron sequestration within cells and reduced iron availability (Soares and Hamza, 2016). Moreover, SARS-CoV-2 infection upregulates the expression of transferrin receptor 1 (TfR1), which enhances iron uptake and accumulation in cells (Zhang et al., 2020). The dysregulated iron metabolism creates a favorable environment for lipid peroxidation and the initiation of ferroptosis.
Oxidative stress is a hallmark of ferroptosis and is closely associated with COVID-19 pathogenesis. Viral infection induces the production of ROS, which overwhelm the cellular antioxidant defense systems, leading to oxidative damage and lipid peroxidation (Dixon et al., 2012). In COVID-19, the combination of viral-induced ROS production, inflammation, and dysregulated iron metabolism amplifies oxidative stress, promoting the occurrence of ferroptosis.
The depletion of glutathione (GSH), a major intracellular antioxidant, is another crucial factor in ferroptosis. GSH acts as a critical regulator of lipid peroxidation by neutralizing lipid hydroperoxides and maintaining redox balance within cells (Dixon et al., 2012). However, in COVID-19, GSH levels are depleted due to increased oxidative stress and the dysregulation of GSH synthesis and regeneration pathways (Muri et al., 2021). The depletion of GSH reduces the cellular capacity to scavenge lipid peroxides, thereby promoting ferroptosis.
Implications for Treatment and Future Directions
Understanding the involvement of ferroptosis in COVID-19 multi-organ complications opens up potential avenues for therapeutic interventions. Targeting ferroptosis-associated pathways may provide new strategies to mitigate the damaging effects of the disease.
Several experimental compounds with ferroptosis-inhibiting properties have shown promise in preclinical studies. These include liproxstatin-1, ferrostatin-1, and deferoxamine, which act by inhibiting lipid peroxidation, scavenging ROS, and chelating iron ions (Dixon et al., 2012; Hassannia et al.,2020).
Additionally, small molecules such as sulfasalazine and vitamin E have demonstrated the ability to protect against ferroptotic cell death by modulating iron metabolism and reducing lipid peroxidation (Bersuker et al., 2019; Magtanong et al., 2019). These compounds could potentially be repurposed for the treatment of COVID-19, particularly in severe cases with multi-organ complications.
Furthermore, the use of antioxidants and anti-inflammatory agents may have beneficial effects in mitigating ferroptosis and its associated organ damage in COVID-19. N-acetylcysteine (NAC), a precursor of glutathione, has been shown to replenish intracellular GSH levels and exert anti-inflammatory effects (Wu et al., 2004).
Other antioxidants such as melatonin and alpha-lipoic acid have also demonstrated potential in modulating oxidative stress and inflammation, thereby protecting against ferroptosis (Shin et al., 2021; Song et al., 2020).
In addition to pharmacological interventions, targeting the upstream regulators of ferroptosis may provide novel therapeutic strategies. For example, inhibition of the nuclear factor erythroid 2-related factor 2 (NRF2) pathway, which regulates the expression of antioxidant and detoxifying enzymes, has been shown to enhance ferroptosis sensitivity (Sun et al., 2016). Therefore, modulating NRF2 activity could be explored as a potential approach to attenuate ferroptosis in COVID-19.
Further research is needed to unravel the intricate mechanisms of ferroptosis in COVID-19 and to identify specific targets for therapeutic intervention. This includes investigating the role of ferroptosis in long COVID and understanding the factors that contribute to its persistence. Additionally, clinical trials are required to evaluate the efficacy and safety of ferroptosis-targeted therapies in COVID-19 patients, considering the complex interplay between viral infection, immune responses, and organ-specific pathologies.
In conclusion, ferroptosis has emerged as a significant player in the multi-organ complications associated with COVID-19. The dysregulation of iron metabolism, oxidative stress, and depletion of antioxidants contribute to ferroptotic cell death, leading to organ damage observed in severe cases. Expanding our understanding of the molecular mechanisms underlying ferroptosis in COVID-19 opens up potential therapeutic avenues to mitigate the detrimental effects of the disease and improve patient outcomes.
very important article to read for further information
The Chemistry of Reactive Oxygen Species (ROS) Revisited: Outlining Their Role in Biological Macromolecules (DNA, Lipids and Proteins) and Induced Pathologies
Living species are continuously subjected to all extrinsic forms of reactive oxidants and others that are produced endogenously. There is extensive literature on the generation and effects of reactive oxygen species (ROS) in biological processes, both in terms of alteration and their role in cellular signaling and regulatory pathways. Cells produce ROS as a controlled physiological process, but increasing ROS becomes pathological and leads to oxidative stress and disease. The induction of oxidative stress is an imbalance between the production of radical species and the antioxidant defense systems, which can cause damage to cellular biomolecules, including lipids, proteins and DNA. Cellular and biochemical experiments have been complemented in various ways to explain the biological chemistry of ROS oxidants. However, it is often unclear how this translates into chemical reactions involving redox changes. This review addresses this question and includes a robust mechanistic explanation of the chemical reactions of ROS and oxidative stress.
reference link :https://www.frontiersin.org/articles/10.3389/fgene.2023.1187985/full