Ergothioneine and COVID-19: Inflammation Research

Ergothioneine & Inflammation

5 proposed anti-COVID mechanisms

In 2020, researchers mapped five distinct pathways by which ergothioneine could reduce COVID-19 severity — none involving direct anti-viral activity. Here is what those mechanisms are, and what the evidence actually supports.

Cheah et al., Antioxidants, 2020

NETosis

neutrophil trap formation blocked via MPO inhibition

ARDS

primary COVID mortality cause the mechanisms target

0

clinical trials testing ergothioneine in COVID patients

Cheah et al., Antioxidants, 2020

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In March 2020, as the first wave of COVID-19 spread globally, the scientists who had spent years studying ergothioneine noticed something uncomfortable. The people dying from COVID-19 were largely elderly, and the elderly are exactly the population with the lowest ergothioneine levels.^[4] Whether that overlap was meaningful or coincidental was impossible to know from the data available. But the mechanisms ergothioneine had been shown to affect — NF-κB activation, neutrophil behavior, endothelial function, oxidative stress in lung tissue — were precisely the mechanisms driving COVID-19's most dangerous outcomes.

A review published in Antioxidants in 2020 by Cheah and colleagues laid out this case carefully.^[1] It was a hypothesis paper, explicitly framed as such, proposing five mechanisms by which ergothioneine might reduce COVID-19 severity. No clinical trial has since tested this hypothesis. The paper's value is not as evidence of a treatment. It is as a coherent mechanistic argument connecting ergothioneine's known biology to COVID-19's known pathophysiology. For a broader introduction to how ergothioneine's transport system and anti-inflammatory mechanisms work, see what ergothioneine is and why your body hoards it.

The 2020 Hypothesis Paper: Five Proposed Mechanisms, Zero Clinical Trials

Cheah and colleagues did not claim ergothioneine was a treatment for COVID-19.^[1] The paper was a mechanistic analysis, written during the early pandemic when researchers across many fields were examining whether existing compounds with relevant biology deserved further investigation. The five mechanisms proposed were:

1. ROS scavenging in inflamed lung tissue. COVID-19 produces a massive burst of reactive oxygen species in lung tissue during the cytokine response. Ergothioneine's antioxidant capacity in the specific redox chemistry of lung inflammation made it a candidate for limiting this oxidative damage.

2. NETosis inhibition via myeloperoxidase blockade. Neutrophils, when over-activated during severe infection, form neutrophil extracellular traps (NETs) — structures made of DNA, proteins, and enzymes that can damage blood vessel walls and contribute to the clotting abnormalities seen in severe COVID-19. Ergothioneine inhibits myeloperoxidase (MPO), the neutrophil enzyme that drives NET formation. Blocking MPO could reduce the magnitude of this response.

3. Prevention of endothelial dysfunction and coagulopathy. COVID-19 damages the inner lining of blood vessels, contributing to the micro-clotting and thrombosis that drove severe cases. Ergothioneine's documented role in protecting vascular endothelial cells from oxidative and inflammatory damage was the mechanistic basis here.

4. Protection against ARDS. Acute respiratory distress syndrome was the primary direct cause of COVID-19 deaths. ARDS involves overwhelming inflammation and fluid accumulation in the lungs. The anti-inflammatory mechanisms ergothioneine demonstrated in cellular studies were proposed as potentially relevant to limiting ARDS progression.

5. Organ protection. Beyond the lungs, severe COVID-19 caused kidney, liver, and cardiac damage. Ergothioneine's antioxidant and anti-inflammatory mechanisms across multiple tissue types made it a theoretical candidate for limiting collateral organ damage.

This list is mechanism-driven, not outcome-driven. These are hypotheses grounded in ergothioneine's established biology, not results from COVID-19 trials. Presenting the paper accurately is important: it is hypothesis-generating research that warranted follow-up, not evidence of efficacy.

The Cytokine Storm Connection: NF-κB and Caspase-1

The specific molecular evidence connecting ergothioneine to COVID-19's most dangerous inflammatory process comes from a 2010 study that predates COVID by a decade.

Cheah and colleagues showed in monocyte cell cultures that ergothioneine blocked H2O2- and TNF-α-driven NF-κB activation and suppressed caspase-1 activation.^[2] NF-κB is the transcription factor that switches on the majority of pro-inflammatory gene expression. Caspase-1 is the enzyme that processes IL-1β into its active, pro-inflammatory form. Both are central to what happens during a cytokine storm: NF-κB amplifies the signal, caspase-1 produces the cytokines that fuel systemic inflammation.

The importance of this finding for COVID-19 is contextual rather than direct. Severe COVID-19 causes a cytokine storm — an uncontrolled inflammatory cascade dominated by TNF-α, IL-1β, IL-6, and related mediators — that causes more damage than the virus itself in many cases. The cytokines ergothioneine was shown to suppress in monocyte cultures are the same cytokines identified as the key drivers of severe COVID-19 mortality. This does not prove ergothioneine would have reduced cytokine storms in COVID patients. It establishes that the compound's mechanism of action targets the same signaling pathways that become pathological in severe disease.

For a deeper examination of these pathways and the 2025 data on NF-κB and JAK/STAT3 suppression, see ergothioneine and anti-inflammatory research.

Endothelial Protection and ARDS: The Mechanisms Most Specific to COVID

Among the five proposed mechanisms, the endothelial protection angle had the strongest existing evidence base at the time of the 2020 paper.

A 2017 review by Servillo and colleagues examined ergothioneine's cardiovascular protective properties, with particular attention to vascular endothelium.^[3] The review documented OCTN1's prominent expression in monocytes and macrophages — the immune cells that infiltrate and damage endothelial tissue during the vascular inflammation characteristic of severe COVID-19. By concentrating ergothioneine specifically in these cells, OCTN1 expression ensures that the immune cells most responsible for vascular damage during COVID also carry high levels of the compound that could limit that damage. The review covered NF-κB suppression in the cardiovascular context and documented ergothioneine's direct protective effects on endothelial cells under oxidative stress.

The NETosis mechanism is particularly relevant to what made severe COVID-19 distinctive. The clotting abnormalities, micro-thromboses, and vascular occlusions seen in severe cases were partly driven by neutrophil extracellular trap formation triggered by MPO activation. Ergothioneine's MPO-inhibiting activity, which the Cheah 2020 paper highlighted, would theoretically reduce the magnitude of this NET-forming response. This is a logical mechanistic chain, but it has not been tested in COVID patients or even in COVID-specific animal models. The MPO inhibition data comes from pre-COVID research in other inflammatory contexts.

Why the Elderly Were Both Most at Risk From COVID-19 and Most Ergothioneine-Depleted

The convergence Cheah and colleagues highlighted in 2020 remains the most compelling human-interest angle in this research.

Cheah and colleagues published a separate cohort study in 2016 showing that blood ergothioneine levels are significantly lower in elderly people with mild cognitive impairment compared to healthy elderly people, and that ergothioneine levels decline progressively with age across the study population.^[4] This age-related depletion has a straightforward biological explanation: older adults eat less, eat fewer mushrooms specifically, and face higher chronic inflammatory burden that pulls ergothioneine into inflamed tissues and away from general circulation.

The population mortality data from the Malmö Diet and Cancer cohort adds further context.^[5] In 3,236 adults tracked over long-term follow-up, higher plasma ergothioneine was associated with 21% lower cardiovascular mortality (HR=0.79, p=0.002) and 14% lower all-cause mortality (HR=0.86, p=4×10⁻⁵). Post-COVID cardiovascular complications became one of the defining long-term health concerns from the pandemic. The population-level evidence that ergothioneine status predicts cardiovascular outcomes is relevant to this, even though no COVID-specific biomarker data exists.

The convergence is not proof of a causal relationship. It is an observation: the people at highest risk from COVID-19 overlap substantially with the people most likely to have low ergothioneine levels. Elderly age, metabolic comorbidities, chronic inflammation, reduced dietary diversity — all of these factors are associated with both greater COVID-19 severity and lower ergothioneine status. Whether the ergothioneine depletion contributed causally to worse outcomes is unanswerable from the available data.

Where the 2025 Evidence Stands

A 2025 comprehensive review of ergothioneine's mechanisms and therapeutic implications updated the picture with five additional years of research.^[6] The review confirmed dose-dependent suppression of TNF-α, IL-1β, and IL-6 via NF-κB, MAPK, and PI3K/AKT pathways in multiple model systems. It noted 30 mg/day as the recommended adult dose based on the available evidence.

What it did not report was any COVID-specific clinical trial data, because none exists. No randomized trial has examined ergothioneine supplementation in COVID-19 patients, COVID-19 severity reduction, or post-COVID inflammatory resolution. The 2025 review addressed ergothioneine's therapeutic potential broadly, covering multiple inflammatory and metabolic conditions, and COVID-19 remains an area where the evidence is purely mechanistic.

For a thorough look at how these same mechanisms apply across chronic inflammatory conditions, including the chronic inflammatory conditions most associated with COVID-19 complications, see ergothioneine and chronic inflammatory conditions.

What Ergothioneine Is Not

Ergothioneine has no demonstrated direct anti-viral activity. It does not block viral replication, inhibit viral entry, or interfere with SARS-CoV-2's mechanisms of infection. Every proposed mechanism in the Cheah 2020 paper operates on the host's inflammatory and oxidative response to infection — not on the virus itself. This distinction matters because COVID-19 supplements were widely misrepresented during the pandemic, and ergothioneine deserves accurate framing.

The anti-inflammatory and antioxidant mechanisms are real and well-documented across multiple tissue types and disease models. The mechanistic case for potential benefit in COVID-19 is coherent. But the leap from "this compound reduces NF-κB activation in monocytes" to "this compound treats COVID-19" requires clinical trial evidence that does not exist for ergothioneine. For context on ergothioneine's biomarker associations with the cardiovascular and cognitive endpoints most relevant to COVID-19 sequelae, see ergothioneine as an inflammatory biomarker.

The Bottom Line

The 2020 hypothesis that ergothioneine could reduce COVID-19 severity was mechanistically coherent, based on five distinct biological pathways, and transparently framed as hypothesis-generating rather than evidence of efficacy. No clinical trial has tested this. The strongest human-relevant observation remains the convergence between COVID-19 risk populations and the populations with the lowest ergothioneine levels. The mechanistic evidence underlying the proposal, including NF-κB suppression, MPO inhibition, and endothelial protection, comes from pre-COVID research in related inflammatory contexts and remains valid as a description of the compound's biology.

Frequently Asked Questions

Did mushrooms help protect against COVID-19?

No clinical trial tested mushroom consumption or ergothioneine supplementation as protection against COVID-19 infection or severity. A 2020 hypothesis paper identified five mechanistic pathways by which ergothioneine might reduce COVID-19 severity, including NF-κB suppression and neutrophil trap inhibition, but these are proposed mechanisms, not tested outcomes.

Can ergothioneine reduce COVID-19 inflammation?

Ergothioneine has demonstrated anti-inflammatory activity via NF-κB, PI3K/AKT, and JAK/STAT3 suppression in monocytes and macrophages — the same cell types central to COVID-19's cytokine storm. Whether this translates to reduced COVID-19 inflammation in humans has not been tested. The mechanistic basis is plausible; the clinical evidence does not exist.

What supplements help with COVID cytokine storm?

No supplement has been proven to treat COVID-19 cytokine storm in randomized trials. Ergothioneine's documented ability to block NF-κB activation and suppress caspase-1 in monocyte cultures is relevant to the molecular targets of cytokine storm, but this connection remains mechanistic only. The compounds that did show clinical benefit in COVID-19 cytokine storm were pharmaceutical drugs, notably dexamethasone and IL-6 receptor blockers.

Does ergothioneine help with long COVID?

No research has specifically examined ergothioneine in long COVID. Long COVID involves persistent post-viral inflammation, fatigue, cognitive impairment, and cardiovascular effects. Ergothioneine's anti-inflammatory and antioxidant mechanisms are theoretically relevant to some of these processes, and the population-level data linking low ergothioneine to cardiovascular mortality and cognitive impairment may be worth noting. But there is no long COVID-specific ergothioneine research.

Is ergothioneine anti-viral?

No. Ergothioneine has no documented direct anti-viral activity. It does not block viral replication or interfere with SARS-CoV-2 infection mechanisms. All proposed mechanisms for COVID-19 relevance operate on the host immune and inflammatory response, not on the virus. This is an important distinction: ergothioneine is an anti-inflammatory and antioxidant compound, not an anti-viral one.

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