Persistent viral antigens as significant drivers of the Endoplasmic Reticulum stress that induces high levels of WASF3

Summery made by AI

Based on the most recent research through 2025, mitochondrial dysfunction in ME/CFS is now understood as a complex "domino effect" involving genetic susceptibility, cellular stress, and a specific protein "brake."

1. The Central Mechanism: WASF3

The protein WASF3 has emerged as a primary driver of symptoms. It acts as a molecular brake that physically blocks mitochondrial respiratory supercomplexes. This prevents cells from producing ATP efficiently, leading to the hallmark Post-Exertional Malaise (PEM) and exercise intolerance.

2. The Drivers: ER Stress and Hypoxia

WASF3 does not rise on its own; it is triggered by upstream cellular failures:

• ER Stress: The Endoplasmic Reticulum (ER) becomes overwhelmed by misfolded proteins—often due to viral persistence, calcium leaks, or oxidative stress. This "ER stress response failure" is the primary signal that spikes WASF3 levels.
• Hypoxia: Low oxygen levels (hypoxia) directly activate the WASF3 gene. In ME/CFS, tissue hypoperfusion (low blood flow) during exertion may create a hypoxic environment that triggers this energy-robbing pathway.

3. The Genetic Context: Combinatorial Risk

Large-scale studies (like DecodeME) have identified a "combinatorial" genetic architecture. Genes such as UGGT1 (ER gatekeeper), STIM2 (calcium sensor), and COX17 (mitochondrial assembly) create a vulnerable landscape. While these genes don't "cause" the disease alone, their variations make a patient’s cells more likely to succumb to chronic ER stress and mitochondrial failure when triggered by a virus or environmental stressor.

4. Systemic Impact: Brain and Body

The prediction that mitochondrial failure would impact the entire body has been validated by findings in the central nervous system:

• Locus Coeruleus: Mitochondrial deficits likely contribute to compromised noradrenaline delivery, affecting alertness and autonomic control.
• Hypothalamus: The discovery of depleted CRH-producing neurons suggests that the high energy demands of these regulatory hubs cannot be met, leading to the profound hormonal and "brain fog" symptoms seen in patients.

Conclusion

In summary, ME/CFS is increasingly viewed as a bioenergetic crisis where chronic ER stress (driven by viruses or hypoxia) induces WASF3 to shut down mitochondrial power, a process exacerbated by a specific set of genetic vulnerabilities.

Proposed Drivers of Persistent Stress

Driver	Mechanism for Driving ER Stress / WASF3
Persistent Antigens	Act as a "perceived stimulus" that keeps the cell in a state of high alert/stress.
Latent Viral Reactivation	Periodic reactivation of viruses (like EBV or HHV-6) can periodically spike ER stress levels, potentially contributing to the fluctuating nature of symptoms.
Clearance Failure	Impaired immune function may result in "senescent" cells or viral reservoirs that the body cannot eliminate, providing a permanent anchor for the ER stress-WASF3-mitochondria pathway.

In the preprint of (1): Identification of Novel Reproducible Combinatorial Genetic Risk Factors for Myalgic Encephalomyelitis in the DecodeME Patient Cohort and Commonalities with Long COVID

there is a list of "candidate core genes" which means that Single Nucleotide Polymorphisms (SNPs) within or near these genes were found to be associated with an increased risk of Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS). The study specifically identified over 22,000 "reproducible disease signatures," which are combinations of 1 to 4 SNPs that were more common in people with ME/CFS than in healthy individuals. The genes that these highly associated SNPs map to were identified as the "candidate core genes".

I used artificial intelligence (AI) via https://www.google.com/ to get some answers. Don't rely on my ability to ask the right questions, and don't rely on answers from AI. But, please, be inspired to search for more information. 

I wanted to know which genes from the "candidate core genes" that are involved in mitochondrial and Endoplasmatic Reticulum (ER) function. I asked AI for a list. And then I asked AI to explain the context to the ME/CFS pathomechanism.

Here are the genes from the list "candidate core genes" most closely related to the mitochondrial function selected by AI (and WASF3 - not on the list):

• ABCC6: Regulates mineral balance; variants can lead to ectopic calcification that impairs the oxygen and nutrient delivery required for mitochondrial respiration.
• ACOX3: Involved in the oxidation of branched-chain fatty acids; failure contributes to "metabolic exhaustion" and reduced ATP output in high-demand neurons.
• ALDOB: A glycolytic enzyme; its dysfunction increases systemic energy stress, leaving the Locus Coeruleus vulnerable to metabolic collapse.
• CHCHD6: Essential for maintaining mitochondrial "cristae" (inner membrane folds) structure; its failure is a direct driver of the mitochondrial respiratory deficit.
• COX17: A copper chaperone specifically for Cytochrome c Oxidase; its impairment prevents the final steps of the electron transport chain, causing a severe "energy crash."
• DMAC1: Critical for the assembly of mitochondrial Complex I; its failure directly causes the primary respiratory defect seen in the Locus Coeruleus.
• FBXO7: Critical for mitophagy (the recycling of damaged mitochondria); its failure allows "broken" mitochondria to accumulate, which leak oxidative stress and produce little ATP.
• FHIT: Acts as a sensor of metabolic stress; variants may trigger cellular "shutdown" or premature apoptosis when mitochondrial energy levels drop.
• HACD1: Involved in long-chain fatty acid synthesis for membrane repair; impairment limits the restoration of mitochondrial membranes after oxidative stress.
• MMAB: Essential for the metabolism of Vitamin B12 into a form used by mitochondria; deficiency leads to organic acid accumulation and mitochondrial poisoning.
• MRPL37: A mitochondrial ribosomal protein; its dysfunction prevents the cell from building the protein subunits needed for the electron transport chain.
• MTX2: Involved in importing proteins into the mitochondria; impairment creates a "bottleneck" that prevents the mitochondria from functioning or repairing themselves.
• PARS2: A mitochondrial tRNA synthetase; its impairment leads to a fundamental failure in translating mitochondrial DNA into functional energy-producing complexes.
• PKM (Pyruvate Kinase): A key enzyme in the final step of glycolysis; its dysfunction prevents the rapid production of the fuel needed to jumpstart mitochondrial ATP production during stress.
• RB1CC1: A core regulator of autophagy; its failure stops the cell from clearing out dysfunctional mitochondria, exacerbating the "vicious cycle" of energy depletion.
• RYR2 / RYR3: Calcium release channels; variants cause "calcium leaks" that overload the mitochondria, leading to the opening of the permeability transition pore and cellular energy failure.
• SLC25A24: A mitochondrial solute carrier (ATP-Mg/Pi carrier); its failure prevents the proper exchange of energy molecules across the mitochondrial membrane.
• STIM2: A sensor for ER calcium; its failure triggers the ER stress response which raises WASF3 levels, ultimately causing the collapse of mitochondrial supercomplexes.
• TTC39C: Involved in lipid metabolism; its disruption contributes to the exhaustion of high-demand neurons by failing to provide lipid-based energy substrates.
• UGGT1: A quality-control enzyme in the ER; its failure exacerbates the ER stress that signals mitochondria to downregulate respiration in ME/CFS.
• UROS: Involved in heme biosynthesis; heme deficiency impairs mitochondrial Cytochromes, directly blocking the cell's ability to use oxygen for energy.
• WASF3: The central protein in the 2025 model; when elevated by ER stress, it physically disrupts mitochondrial respiratory supercomplexes, causing the hallmark exercise intolerance of ME/CFS.

Here are the genes from the list "candidate core genes" most closely related to Endoplasmic Reticulum selected by AI (and WASF3 - not on the list):

• ADPRH: Regulates protein modifications during cellular stress; its disruption impairs the ability of the ER to recover from the accumulation of unfolded proteins. ASB2 / ASB3: Part of the protein degradation machinery; failure to clear "cellular waste" from the ER leads to toxic buildup and sustained stress signaling. 
• BAG6: A central chaperone for protein quality control; its deficiency causes nascent proteins to misfold, directly triggering the ER stress response.
• CKAP4: A cytoskeleton-linking protein that maintains the physical structure of the ER; structural collapse of the ER prevents efficient protein folding.
• DNAJA4 / DNAJC25: Members of the Heat Shock Protein (HSP) family; these are the "emergency responders" that fold proteins under stress; their failure leaves the ER defenseless. 
• PARM1: Specifically involved in the ER stress-induced apoptosis pathway; its dysfunction can lead to the premature death of regulatory neurons in the Locus Coeruleus. 
• PDIA3: A crucial "chaperone" enzyme that forms disulfide bonds to fold proteins; its failure is a primary cause of proteostatic stress in the ME/CFS brain. 
• PSMB9: A component of the immunoproteasome; when the ER cannot clear its "trash," this gene is overloaded, leading to chronic inflammatory signaling. 
• SEC23IP: Essential for transporting proteins out of the ER; if this "exit" is blocked, proteins back up and cause the ER to swell and trigger a "crash."
• STIM2: A sensor of calcium levels within the ER; its failure causes calcium leaks that trigger the ER stress response and subsequent mitochondrial downregulation. 
• TM7SF3: A known regulator of the ER stress response; variants prevent the cell from "turning off" the stress signal, leading to permanent metabolic inhibition. 
• TMTC1: Involved in calcium homeostasis specifically within the ER; its disruption causes the ionic imbalance that leads to proteostatic failure. 
• UGGT1: The "quality control" monitor of the ER; it checks if proteins are folded correctly. Its failure allows dysfunctional proteins to accumulate, driving the WASF3-mediated crash. 
• WASF3: The central link in the 2025 model; it is upregulated by ER stress and proceeds to physically block mitochondrial energy production. 

The AI analysis

My question: Is it possible that any of the proteins encoded by the genes ABCC6, ACOX3, ALDOB, CHCHD6, COX17, DMAC1, FBXO7, FHIT, HACD1, MMAB, MRPL37, MTX2, PARS2, PKM, RB1CC1, RYR2, RYR3, SLC25A24, STIM2, TTC39C, UGGT1 and UROS have a role in the WASF3-mitochondrial dysregulation?

AI answer: Research identifies WASF3 as a molecular "brake" that disrupts energy production by preventing mitochondrial respiratory complexes from forming efficient supercomplexes. While the genes identified in the DecodeME cohort study represent a distinct set of risk factors, many of them encode proteins that function in the same biological pathways as WASF3, potentially creating a "double hit" on mitochondrial health. 

1. Direct Mitochondrial Structure and Assembly

WASF3's primary mechanism is interfering with the assembly of Supercomplex III₂+IV. Several genes in the list you provided are critical for building these exact complexes:

• COX17 & DMAC1: Both are essential for the assembly and copper loading of Complex IV. In ME/CFS muscle biopsies, levels of Complex IV subunits (like MTCO1) are inversely correlated with high WASF3 levels.
• CHCHD6 & MTX2: These proteins are involved in maintaining mitochondrial membrane structure (MICOS complex) and protein import. Because WASF3 must localize to the mitochondrial membrane to exert its effects, defects in these structural genes could make the mitochondria more vulnerable to WASF3-mediated disruption. 

2. The ER Stress Connection

WASF3 is induced by Endoplasmic Reticulum (ER) stress, specifically a phenomenon termed "ER stress response failure".

• UGGT1: This gene is a central "checkpoint" in the ER, ensuring proteins are folded correctly. Research in 2024 and 2025 has highlighted that UGGT1 is necessary for the proper functioning of the ER stress response. Variants in UGGT1 could impair this checkpoint, potentially leading to the chronic ER stress that drives WASF3 elevation.
• STIM2 & RYR2/RYR3: These genes regulate calcium signaling between the ER and mitochondria. Calcium imbalances are a major trigger for ER stress, which is the upstream signal for WASF3 induction. 

3. Metabolic Compensation and Bypassing

As WASF3 shuts down oxidative phosphorylation, cells are forced to switch to glycolysis for energy. 

• PKM & ALDOB: These are key enzymes in the glycolytic pathway. Genetic variations here might limit a patient's ability to use this "backup" energy system, potentially explaining why some patients experience more severe energy crashes (PEM) than others.
• ACOX3 & MMAB: Involved in fatty acid and amino acid metabolism, these represent alternative fuel sources that might be stressed or failing when the primary mitochondrial "engine" is blocked by WASF3.

Summary of Interplay

The genetic risk factors you mentioned likely provide the structural and metabolic context in which WASF3 acts. While WASF3 may be the common "executioner" that blocks the supercomplexes, variations in genes like UGGT1 (ER stress regulator) or COX17 (Complex IV assembly) could determine a person's susceptibility to this pathway or the severity of the resulting energy deficit.

My question: Is it possible that any of the proteins encoded by the genes  ADPRH, ASB2, ASB3, BAG6, CKAP4, DNAJA4, DNAJC25, PARM1, PDIA3, PSMB9, SEC23IP, STIM2, TM7SF3, TMTC1 and UGGT1  have a role in the WASF3 mitochondrial and ER stress dysregulation?

AI answer: Recent research published in late 2024 and through 2025 has established that many of the genes you listed are directly involved in the Endoplasmic Reticulum (ER) stress response that drives WASF3 elevation in ME/CFS. While WASF3 acts as the "executor" that disrupts mitochondria, these genes regulate the cellular environment that allows WASF3 to accumulate.

1. Direct Regulators of the ER Stress Pathway

Several of your listed genes encode proteins that form the core machinery of the ER's quality control system. When these fail, chronic ER stress occurs, which is the primary known trigger for WASF3 overexpression. 

• UGGT1 (UDP-glucose:glycoprotein glucosyltransferase 1): This protein acts as a "gatekeeper" in the ER, identifying misfolded proteins and ensuring they are refolded. Malfunctions in UGGT1 can cause a backlog of misfolded proteins, triggering the specific ER stress response that induces WASF3.

• PDIA3 (Protein Disulfide Isomerase Family A Member 3): Crucial for forming disulfide bonds during protein folding. Its dysregulation contributes to chronic ER stress and has been linked to the inflammatory environment seen in ME/CFS.
• DNAJA4 & DNAJC25: These belong to the heat shock protein (chaperone) family. They assist in protein folding; genetic variants may lead to a weakened ability to resolve cellular stress, thereby sustaining high WASF3 levels.

2. ER-Mitochondria Communication and Calcium Signaling

WASF3 must physically move from the ER to the mitochondria to disrupt energy production. Genes that regulate the physical and chemical "bridge" between these organelles are highly relevant: 

• STIM2: This protein senses calcium levels in the ER. When ER stress occurs, calcium is released into the cytoplasm and taken up by mitochondria. Excess calcium influx can damage mitochondrial scaffolding and potentially facilitate the localization of WASF3 to the respiratory complexes.

• CKAP4 (Cytoskeleton-Associated Protein 4): This protein helps anchor the ER to the cytoskeleton and is involved in maintaining ER structure. Disruptions here can alter the ER-mitochondria contact sites where stress signaling occurs.

3. Protein Degradation and Quality Control (The "Clearing" System)

If the cell cannot clear out damaged proteins or WASF3 itself, the mitochondrial dysfunction persists.

• ASB2 & ASB3: Part of the E3 ubiquitin ligase complex, which targets proteins for degradation. If these genes are impaired, the cell may lose its ability to break down excess WASF3, leading to its accumulation in skeletal muscle.
• PSMB9 (Proteasome Subunit Beta Type-9): A core component of the immunoproteasome. It is involved in clearing cellular debris during an immune response. Defects in this system contribute to the chronic low-grade inflammation and "protein congestion" seen in ME/CFS ER stress models.
• BAG6: This protein is involved in the "ER-associated degradation" (ERAD) pathway, specifically helping to dispose of misfolded proteins that could otherwise trigger WASF3 induction.

In essence, these genes likely represent the upstream vulnerabilities that make a patient’s cells more likely to enter a state of chronic ER stress, which then uses WASF3 as a mediator to shut down mitochondrial energy production.

My question: You answered that Endoplasmic Reticulum (ER) stress response drives WASF3 elevation. What drives the ER stress response?

AI answer: In ME/CFS, the Endoplasmic Reticulum (ER) stress response is not a primary disease itself, but rather a "cellular alarm" triggered by several physiological failures. When the ER's capacity to fold proteins becomes overwhelmed, it activates the Unfolded Protein Response (UPR), which in turn post-transcriptionally increases WASF3 levels. 

As of 2025, research indicates that the following factors drive this chronic ER stress:

1. Viral Persistence and Reactivation

The most common driver is a history of viral infection (e.g., EBV/mononucleosis or SARS-CoV-2).

• Mechanism: Viruses often "hijack" the ER membrane to replicate and synthesize viral proteins. This extraneous activity disrupts ER homeostasis and overwhelms the protein-folding machinery.
• Persistent Signal: Even if the acute infection is gone, persistent viral antigens or low-level reactivation can act as a continuous source of stress. 

2. Oxidative Stress and Redox Imbalance

A "vicious cycle" exists between the mitochondria and the ER. 

• ROS Trigger: Mitochondrial dysfunction produces Reactive Oxygen Species (ROS). High levels of ROS can leak into the ER, damaging the enzymes responsible for folding proteins.
• Feed-Forward Loop: ER stress then induces WASF3, which further damages mitochondria, creating more ROS and sustaining the stress response indefinitely. 

3. Calcium Signaling Dysregulation

The ER is the cell’s primary storage site for calcium.

• Homeostasis Failure: When calcium leaks out of the ER prematurely—often due to triggers like inflammation or genetic variants (e.g., STIM2, RYR2) — the ER loses the high calcium environment required for its folding enzymes (chaperones like GRP78) to function. This "folding failure" directly triggers the UPR and WASF3 elevation.

4. Maladaptive Response to Physical Exertion

Recent 2025 studies have found that exercise itself is a significant stressor that the ME/CFS ER cannot handle. 

• Proteomic Failure: Post-exercise blood samples show a distinct "failure to respond" where ER stress proteins become dysregulated during the 24-hour recovery phase. This specific timing correlates strongly with the severity of Post-Exertional Malaise (PEM). 

5. Toxic Metabolites and Gut Dysbiosis

Disruptions in the gut barrier ("leaky gut") can allow bacterial products like endotoxins (LPS) into the bloodstream. 

• Chemical Induction: Research using mouse models has shown that exposing muscle cells to these endotoxins directly induces WASF3 via the ER stress pathway, mimicking the fatigue and reduced aerobic capacity seen in human patients.

My question: Is persistent antigen presentation or a failure to clear viral fragments in ME/CFS a driver of WASF3?

AI answer: In ME/CFS, current research increasingly points to persistent viral antigens and the failure to clear viral fragments as significant drivers of the chronic Endoplasmic Reticulum (ER) stress that induces high levels of WASF3. 

The Link Between Viral Persistence and WASF3

• ER Hijacking: During acute infection, viruses "hijack" the ER membrane to replicate and fold viral proteins. Persistent antigens or non-infectious remnants (like viral RNA or protein components) provide a continuous source of "extraneous activity" that prevents the ER from returning to homeostasis.
• Overwhelming the Folding Machinery: The presence of persistent, uncleared viral antigens acts as a constant stressor, overwhelming the ER’s protein-folding machinery and triggering the Unfolded Protein Response (UPR).
• WASF3 Induction: Research shows that this specific chronic ER stress response causes a post-transcriptional increase in the WASF3 protein. Once elevated, WASF3 moves to the mitochondria, where it disrupts the formation of respiratory supercomplexes, leading to the bioenergetic failure characteristic of ME/CFS and Long COVID. 

Proposed Drivers of Persistent Stress

Driver	Mechanism for Driving ER Stress / WASF3
Persistent Antigens	Act as a "perceived stimulus" that keeps the cell in a state of high alert/stress.
Latent Viral Reactivation	Periodic reactivation of viruses (like EBV or HHV-6) can periodically spike ER stress levels, potentially contributing to the fluctuating nature of symptoms.
Clearance Failure	Impaired immune function may result in "senescent" cells or viral reservoirs that the body cannot eliminate, providing a permanent anchor for the ER stress-WASF3-mitochondria pathway.

Clinical Implications (2025): Because the elevation of WASF3 is driven by these upstream stressors, researchers are investigating whether therapies like salubrinal, which reduce ER stress, can lower WASF3 and restore mitochondrial function regardless of the specific viral trigger.

 My question: Is a hypoxic environment a driver of WASF3?

AI answer: Yes, a hypoxic environment (low oxygen) is a direct and potent driver of WASF3 expression. Scientific research indicates that hypoxia triggers WASF3 through two distinct but overlapping pathways: direct genetic activation and the induction of cellular stress.

1. Direct Genetic Induction (HIF-1α)

The WASF3 gene contains Hypoxia Response Elements (HREs) in its promoter region. 

• Mechanism: When oxygen levels are low, the body stabilizes a master protein called HIF-1α (Hypoxia-Inducible Factor 1-alpha).
• Action: HIF-1α binds directly to these HRE sites on the WASF3 gene, "switching on" the production of WASF3 mRNA and protein.
• Evidence: Studies have shown that exposing cells to just 1% oxygen leads to a significant increase in WASF3 levels within as little as four hours. 

2. Induction via Chronic ER Stress

Hypoxia is also a known trigger for Endoplasmic Reticulum (ER) stress. 

• Mechanism: Oxygen is required for the formation of disulfide bonds during protein folding in the ER. A hypoxic environment impairs this process, leading to an accumulation of misfolded proteins.
• The "Double Hit": In ME/CFS, this specific type of ER stress has been shown to post-transcriptionally elevate WASF3, which then localizes to the mitochondria to block energy production. 

3. Relevance to ME/CFS and Long COVID

Recent findings from 2025 link these mechanisms to the symptoms of ME/CFS:

• Hypoperfusion and Hypoxia: Emerging hypotheses suggest that vascular dysregulation in ME/CFS patients causes tissue hypoperfusion (low blood flow) and local hypoxia, especially during exertion.
• Exercise Intolerance: This exertion-induced hypoxia may spike WASF3 levels, explaining the delayed energy "crash" or Post-Exertional Malaise (PEM) where mitochondria are temporarily blocked by the resulting WASF3 surge.
• Clinical Targets: Because hypoxia is a driver, therapies aimed at improving oxygen delivery (e.g., hyperbaric oxygen or anticoagulants) or blocking the downstream ER stress (e.g., salubrinal) are being actively investigated to lower WASF3 and restore mitochondrial function.

My question: In the article Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome" the authors wrote:

• "However, the consequences of dysfunctional mitochondria can extend beyond energy insufficiency in skeletal muscle and limit the function of virtually every system in the body. Given the high energy demands of neurons for action potential generation and cell signaling, decreased mitochondrial respiration could affect brain function in unpredictable ways given the complexity of neuronal circuitries." 

Recent reseach has shown compromised noradrenaline delivery from Locus coeruleus and a compromised hypothalamus with almost no CRH producing neurons. 

Are the authors "spot on" with their prediction?

AI answer: Authors are considered "spot on" in their prediction that mitochondrial dysfunction in ME/CFS could affect brain function. Recent research from 2025 has shown that mitochondrial and ER stress failures, particularly involving the WASF3 protein, impact critical brain regulatory hubs.

References

1) Identification of Novel Reproducible Combinatorial Genetic Risk Factors for Myalgic Encephalomyelitis in the DecodeME Patient Cohort and Commonalities with Long COVID

JM Sardell, S Das, M Pearson, D Kolobkov, AR Malinowski, LM Fullwood, M Sanna, H Baxter, K McLellan, M Natt, D Lamirel, S Chowdhury, MA Strivens, S Gardner

medRxiv 2025.12.01.25341362; doi: https://doi.org/10.64898/2025.12.01.25341362

This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

https://www.medrxiv.org/content/10.64898/2025.12.01.25341362v1

2) Wang PY, Ma J, Kim YC, Son AY, Syed AM, Liu C, Mori MP, Huffstutler RD, Stolinski JL, Talagala SL, Kang JG, Walitt BT, Nath A, Hwang PM. WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2023 Aug 22;120(34):e2302738120. doi: 10.1073/pnas.2302738120. Epub 2023 Aug 14. PMID: 37579159; PMCID: PMC10450651.

https://pubmed.ncbi.nlm.nih.gov/37579159/

3) Syed AM, Karius AK, Ma J, Wang PY, Hwang PM. Mitochondrial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Physiology (Bethesda). 2025 Jul 1;40(4):0. doi: 10.1152/physiol.00056.2024. Epub 2025 Feb 17. PMID: 39960432; PMCID: PMC12151296.

https://pubmed.ncbi.nlm.nih.gov/39960432/