The Art and Science of Mega-Dose Thiamine Lecture: Part 1
EONutrition – Elliot Overton (nutritionist) – Video 1:34:21
This is the first of two lectures I gave to a group of medical/health professionals on the clinical application of high-dose vitamin B1. In this video I outline the basics of how the body uses this nutrient, why deficiency is likely more prevalent than it is conventionally thought to be, and how high doses may be working via different mechanisms to improve chronic health issues.
https://www.youtube.com/watch?v=-Uf1D2KdTn0
HDT = High Dose Thiamine
Synopsis (with time-code)
*) Video 5.55’’: The system affected by thiamine deficiency
*) +/ 6.00”: Symptoms of beriberi
*) 11.00”: Prevalence of B1 deficiencies (by ordinary people)
*) 12.30”: Medical dogma (incorrect)
Deficiency easily detected by blood test.
*) 14.00”: Common causes of deficiencies (classical risk factors)
*) 15.00”: Most tests are inaccurate
*) 22.00”: You’re out of the box (optimal status)
*) 23.45”: Hormones matters (reference site)
*) 24.25”: Everybody consuming high carbs will suffer from thiamin insufficiency. But not only.
See Figure.
Mind refined foods, inflammation or infection, environmental toxicity, surgery, etc. It increases the demand or it counteracts the enzymatic system. It increases the demand above the board (> 70%).
A appropriate diet is going to sustain you well but – surrounded by so many stresses – to rely on diet solely is not enough / inappropriate.
Many people can’t recover from a pathology because some medications impact the assimilation or the biodisponibility of vitamins.
*) 29.15”” The status of thiamin depends on the level of carbs eaten, even if not refined. High intake of macronutrients in the absence of micronutrients leads to health problems.
*) 30.00”: Recap
*) +/ 31.00”: Metabolic pathway of energy
If you haven’t enough vitamin (TPP, in blue = B1), you can’t use enzymes (yellow).
*) 32.00”: Same evidence: TPP (B1) is needed for carburation.
Figure.
TTP is needed by enzymes required in cellular energy. A continual supply must be brought. Thiamin is a rate-liming factor for energy production: With insufficient B1, the enzymes are effectively blocked and the entire process of energy production slows down. This is central in the process energy at practically at all energy level of the cells (mitochondria).
*) 32.55”: Krebs cycle.
Another figure to represent glycolysis
*) 33.05”: TCA cycle – Without enough thiamin, pyruvate spills into lactate (acidosis).
*) +/ 35.00” Enzyme pathway with B1
*) 35.45””: Thiamin is dependent on magnesium (activation), like many vitamins.
*) 39.05” Vagus nerve. Pathway involved in vagus nerve stimulation. Link with most visceral organs.
*) 39.30” – 44.20” Cholinergic anti-inflammatory pathway
Figure.
Several studies show that the decrease in cholinergic neuron activity correlates with the degree of severity of many neuron pathologies. It inhibits the release of pro-inflammatory cytokines. So, choline indirectly plays a role of modulator against inflammation. The vagus nerve is well the most determinant communicant factor in immune response.
If you lose the ability to communicate the signal from the brain through the vagus nerve, it will take an eternity to recover. Consider too that there is a two-ways communication. Without effective communication between sympatric and para-sympatric brain, we lose the ability to modulate an adaptive response. The system controls itself through the vagus nerve.
*) 44.20” Thiamine, a universal stress molecule.
Extra high thiamine levels protect the cell against injury (upregulation of recovery process), inflammation and oxygen stress.
*) 50.00” The effect of hypoxia on the brain due to a lack of thiamin cofactor
Figure with Krebs cycle and enzymes sensitive to B1 deficiency: TPP & ketoglutarate dehydrogenase.
=> Damage to neurons & mitochondrial dysfunction (reduced ATP production and oxidative stress).
*) 55.00” Book
*) 1.03” Recap
*) 1.04” References
*) 1.14” Enzyme Inhibitors (KGDHC inactivation) lead to problems
KGDHC = α-ketoglutarate dehydrogenase complex (mitochondrial enzyme depending on thiamine)
*) 1.15.45” figure. Thiamine chemistry is disrupted by environmental stress
*) 1.16.55” Figure. Enzyme inhibition
*) 1.1845””. Figure. High dose nutrient therapy
If you saturate the cell with a huge amount of thiamin, it doesn’t account (no problem). You’ll speed the process up.
*) 1.21.45: blood test and company
*) 1.23.16” Effective dose for different forms of thiamine
Type of vitamin effective amount
Thiamine HCL 500 – 4000 mg / day
Benfotiamine 300 – 1800 mg / day
TTFD 100 – 1500 mg / day
*) 1.26.21””: Paradoxical reaction: Temporary worsening of symptoms (from left to right side)
Don’t begin with a high transition (from 500 to 2 000 mg B1) because 80 % people will feel horrible.
People who’ve been deficient since a long time (10 years or more without taking a supplement and eating refined carbs with pasta, bread and / or rice) are more susceptible to encounter body reactions. Idem if you suffer from a chronicle disease (since B1 has been exhausted or in a very limited amount to assure all neuronal tasks). So open a 500 mg capsule and start with a portion of the powder, if required, and don’t jump to 2 000 mg at once. Begin very low and start very slow: Make transition (baseline on the graph). Only raise the dose when the baseline brings an improvement in symptoms and consolidate before raising again. Of course, we don’t raise the dose if someone feel worse; otherwise it’s going to make the situation 10 times worse. We stop taking B1 until we recover. We must be then patient and begin again with a very low dose, before building up very progressively.
*) 1.29.25”: Thiamine nutritional interactions
*) 1.30.25”: How to deal with HDT
Preferably high bioavailability of Thiamine (TTFD). A b-complex will be needed. Potassium and magnesium too. Mg is very important, especially to avoid the paradoxical effect. 1 000 to 2 000 mg more potassium could be helpful too (or coconut water if you don’t want to).
Note 1: If problem with TTFD (neuronal exacerbation), take another form.
Note 2: Do not take a B-50 complex alone every day (cell overgrowth stimulation)
*) 1.32.55’ Info (book):
Mega-Dose Thiamine – Beyond addressing deficiency. Elliot OVERTON

About High dose thiamine (HDT)
I know we have to reach 1500 mg B1 to see some neuro-improvements (through the vagus nerve).
But it's not advised to do it without staples (every 10 days), with 200-300 mg takes.
Of course, according to your feeling, the staple can be prolonged. Or perhaps you'll have to go back to 2 former staples whenever you feel "disconnected" / upset. Overton advises to stop the supplementation completely before taking it again, at the beginning of the process.

Take Dr Allil overton and Chandler Marrs as references. Details on next post

Excerpt from the video of Allil Overton
1.23.16” Effective dose for different forms of thiamine
Type of vitamin effective amount
Thiamine HCL 500 – 4000 mg / day
Benfotiamine 300 – 1800 mg / day
TTFD 100 – 1500 mg / day
*) 1.26.21””: Paradoxical reaction: Temporary worsening of symptoms (from left to right side)
Don’t begin with a high transition (from 500 to 2 000 mg B1) because 80 % people will feel horrible.
People who’ve been deficient since a long time (10 years or more without taking a supplement and eating refined carbs with pasta, bread and / or rice) are more susceptible to encounter body reactions. Idem if you suffer from a chronicle disease (since B1 has been exhausted or in a very limited amount to assure all neuronal tasks). So open a 500 mg capsule and start with a portion of the powder, if required, and don’t jump to 2 000 mg at once. Begin very low and start very slow: Make transition (baseline on the graph). Only raise the dose when the baseline brings an improvement in symptoms and consolidate before raising again. Of course, we don’t raise the dose if someone feel worse; otherwise it’s going to make the situation 10 times worse. We stop taking B1 until we recover. We must be then patient and begin again with a very low dose, before building up very progressively.

Synopsis of the video on next post

@Samyo said in Bacteria creating overgrowth of b12:

@Samyo .

uncomplete. Give the fork (low / high level if you hope a comment.

@jakeseeds said in Thiamine and Magnesium timing:

So when would you advise taking the Mg,

I take magnesium bisglycinate, the one I prefer (glycine, Gaba-like effect). High effectiveness. Choose a powder that mixes well (dilution). Not HSN. mine comes from nutrixeal.com (French site).
Against stress, it's no use to take Mg before a stressful event.
I take it after. 300 mg Mg element is advised then. +/ 16% => 2 g powder. High bioavailable. See the chart.

This kind of magnesium is best absorbed with food but I take it whenever I want / if necessary.
We need 4200 Mg element. Must be in balance with other nutrients: K/Na and Ca/Mg ratio.
It is often advised to take 2 x 300 mg Mg element /day. 3x/day if stress or anxious. In cure.
NB: 300 mg Mg element = 4800 mg powder of Mg bisglycinate (it contains 16% Mg element).
Exception: If your level vitamin D3 is too low (under 45 ng), do not take a high dose Mg on a regular base. Only punctually.
Personally, on a regular base, I check with my diet-software to approach 4500 mg/day.
between 1.25 and 2 g powder 2x/d according to what I've eaten. Often 2 g.
You can take Mg with vitamin B.

For other comment about B1. Tomorrow. Too late here.

@jakeseeds said in Thiamine and Magnesium timing:

I was looking to start taking Thiamine (TTFD) paired with Mg Glycinate and a B complex.

I won't take a B50 complex every day. I take 2x/wk.
As you didn't tell much about your purpose / problem, I'm not going to develop.

@jakeseeds

I suppose it's for optimizing the energy level. If it's for another purpose (brain), it doesn't change the recommendations, as it's supposed to enhance a better carburation.
Thiamine before breakfast and lunch, preferably 15' before the meal.
=> Energy requires B1 B2 B3, especially B1. Not only.
You're going to burn more B2 if you take HD B1. Not necessarily every day for B2.

Figure: See the circle "Citric acid cycle"

2 steps
*) Step one: Carbs / glucose => Pyruvic acid => Acetyl CoA
Vitamins B to produce pyruvic acid and acetyl CoA
https://pmc.ncbi.nlm.nih.gov/articles/PMC7019700/
Which vitamin converts glucose to pyruvate?
=> B3 (NAD)
Which vitamins convert pyruvate to acetyl CoA?
=> B1 B2 (FAD) B3 B5 (pantothenic acid)
Briefly, macronutrients are oxidized (step one) into acetyl-CoA through several pathways including glycolysis, which produces pyruvate from glucose, and vitamins B1, B2, B3, B5 and C play important roles.
*) Step two: Acetyl CoA => Citric Acid Circle (Krebs circle)
Which vitamins are required to pass through Acetyl CoA to Citric Acid Circle?
=> B1 B2 B3 B5.
=> + other B vitamins (B6 B8 B12) and Fe Mg
Then acetyl-CoA enters the citric acid cycle (step two), which generates energy as NADH and FADH2 through a series of eight oxidations that involve vitamins B1, B2, B3, B5, B6, B8 and B12 as well as iron and magnesium.
*) Step three: Energy production
Finally, the electrons of NADH and FADH2 are transferred to the electron transport chain (step 3), where they provide energy used to generate ATP molecules; this step needs the input of vitamins B2, B3, B5 and of iron.
Source: https://pmc.ncbi.nlm.nih.gov/articles/PMC7019700/
Vitamins and Minerals for Energy, Fatigue and Cognition: A Narrative Review of the Biochemical and Clinical Evidence. 2020 doi: 10.3390/nu12010228

If I try to summarize:
Energy metabolism in two steps
Step 1 is the catabolic breakdown of carbs, fat, and protein to extract energy in the form of electrons.
Step 2 is the translation of that energy into ATP using oxygen.

*) Energy and nutrients needed for metabolism

• Carbs => Pyruvic acid => Acetyl CoA: Mg, B1 B2 (FAD) B3 (NAD) + B5
  Required nutrients to extract energy in the form of electrons (electrons in the transport chain) (= oxidative phosphorylation => oxidation-reduction reactions are vital for ATP synthesis)
• Acetyl CoA => Citric Acid Circle (Krebs circle): B1, B2 (FAD), B3 (NAD), Mg, Mn, Fe, GSH + B5
  https://coremedscience.com/blogs/wellness/what-vitamins-give-you-energy
  https://www.nature.com/scitable/topicpage/nutrient-utilization-in-humans-metabolism-pathways-14234029/

Note1: If you take a high dose (HD) of one element, you may encounter problems elsewhere. Here HD B1 => Some B2 required. Otherwise it would be as if you were lacking B2 (exhausted).

Note 2:

Proportions of vitamins B

• the same quantity of vit B1, B2 and B6.
• at least 4 x more vit B3
• at least 2 x more vit B5
  Source : Zoelho.com (in French) Pharma-Dr.

Pay attention:
*)Some people feels nervous when taking high dose of B6 Pyridoxine (PNP). Unbalanced nervous system. DA 2 – 3 mg B6. Orthomolecular pharmacology 10 – 50 mg.
*)Feels better with Benfotiamine or Thiamine HCL than with TTFD (thiamin tetrahydrofurfuryl disulfide). TTFD passes the BBB.
*) B3. The form to privilege is niacinamide
Niacin has different names
Niacin = generic name
Nicotinic acid = pyridine-3-carboxylic acid.
Nicotinamide = niacinamide or pyridine-3-carboxamide
Other derivatives: e.g. nicotinamide riboside

Keep in mind: You’re artificially changing the system by adding extra dose of something, without taking into account the possible side-effects. But if you can listen to your body, why not if you want to experiment …

@nicemushroom17 said in Ears flushing:

I think it's connected to histamine,

I've been dealing with histamine, an overgrowth of intestinal bacteria and a lazy MMC (poor interprandial bowel movement leading to pooping only once).
The last two ones are off. Histamine is under control, but still with a supplement (DAO enzymes).

@AinmBeo said in Consensus on a good Vitamin C source?:

Do you have the link to that post from haidut?

I didn't find it back (20% glycine absorbed)
But I have these sources from Julien Venesson, in French (translor needed if details required). Trustful.
Apport de collagène en poudre selon l'âge (Collagen powder intake according to age)
https://www.julienvenesson.fr/glycine-collagene/#:~:text=Le collagène et la glycine amélioreraient les gains de masse musculaire&text=Le collagène est une protéine de structure qu'on retrouve,selon la pression du sang.

Si glycine pure : 8 à 15 g par jour environ

=> (+/ 10 gr pour 70 Kg)

If pure glycine: approximately 8 to 15 g per day (+/ 10 g for 70 kg / 140 Lb)
https://www.julienvenesson.fr/quels-sont-les-bienfaits-de-la-glycine-en-complement-alimentaire/
https://www.julienvenesson.fr/faut-il-se-supplementer-en-glycine-ou-en-collagene/

Si collagène hydrolysé : 20 gr par jour (If hydrolyzed collagen: 20 gr per day)
https://www.julienvenesson.fr/faut-il-se-supplementer-en-glycine-ou-en-collagene/

Consensus on a good Vitamin C source?

• iHerb.com: Doctor's Best – Pure Vitamin C Powder with Q-C
Doctor's Best, Poudre de vitamine C pure avec Q-C, 250 g (8.8 oz.) 23€ / +/ 20 $ in January 2025
NB: Scottish source (labo DSM) when you see the label Q-C.

Useful Info when Buying Vitamin C
https://mirzoune-ciboulette.forumactif.org/t1884-achat-de-vitamine-c-et-caracteristiques#26178
We are going to group together in this post the characteristics published on several posts on this forum (in French, translator needed)
 Vitamin C dosage
 What to pay attention to when purchasing?
 Where do you buy vitamin C?

@oliveoil said in Consensus on a good Vitamin C source?:

Acerola powder is extremely rich in vitamin c, half a gram gives you the whole daily value.

yes, but remind that 500 g acerola is not 500 g L-ascorbic acid. +/ 20% vit C.
And if it mentions more on the product, it's a fake (lie) or a possible "poison" (half effective vitamin C added => not recognized by the body / cell fouling).

@Mossy said in Consensus on a good Vitamin C source?:

I assume gelatin powder or straight glycine could replace

Yes, when taking 10 g glycine, you only assimilate 2 g (20 %). (Study given by Haidut)
I'd take the half dose in the shake (5 g powder).

@BearWithMe said in Safe laxative when taking blood thinners, diuretics and blood pressure medications?:

Vitamin C is contraindicated with blood thinners I think

Yes, indeed with high dose. in once. Would be more secure to limit it if another solution is possible.
Can you take vitamin C with blood thinners?
Warfarin (Coumadin) -- There have been rare reports of vitamin C interfering with the effectiveness of this blood thinning medication. In recent follow-up studies, no effect was found with doses of vitamin C up to 1,000 mg per day.

@Mossy said in Consensus on a good Vitamin C source?:

I'm curious of your opinion about Peat's dislike of glutamine.

Yes, glutamine in excess (when taking a supplement) could take the pathway glutamate, which is an excitatory substance for the brain. Not desired when in excess. That’s the excitatory side, which is counterproductive when the balance is not reached.
On the other way, we need glutamine as material for the border brush of the intestinal wall. That's the usual material.
We have to find a right equilibrium. Low doses and a moderator like glycine and taurine. Glycine as a gaba-like affect; taurine as an anti-oxidant and so much more – very much more for the brain.

My shake (100-120 ml water or in orange juice), this evening:
1/8 tsp taurine
¼ tsp glutamine
2/3 dose magnesium bisglycinate ( 1 dose = 2.5 g)
1 tsp collagen (glycine)
¼ tsp calcium citrate if required (if under 850 mg Ca) but not every day, of course (…). CaPh would be a better choice if ---

Edit: Glutamine powder becomes / could become only glutamate when passing through the border brush (if no used up).

Reminder:
Taurine as a neuro-protector and moderator of excitotoxicity (1)
Taurine exerts its neuroprotective functions against glutamate-induced excitotoxicity, particularly the glutamate-induced increase in intracellular calcium levels.
Taurine also serves to maintain the structural integrity of the membrane [6], to regulate calcium binding and transport [7, 8], as an osmolyte [9, 10], neuro-modulator [11], neuro-transmitter [12–18] and neuro-protective against neurotoxicity induced by L-glutamate (L-Glu) [19, 20]. Excuse for so little!
Sources and references:

1. Role of taurine as neuro-enhancer, transmitter and protector against the neurotoxicity of glutamate.
   Wu, JY., Prentice, H. Role of taurine in the central nervous system. J Biomed Sci 17 (Suppl 1), S1 (2010). https://doi.org/10.1186/1423-0127-17-S1-S1
2. What makes taurine so important? (in French, translator needed)
   https://mirzoune-ciboulette.forumactif.org/t1840-quest-ce-qui-rend-la-taurine-si-importante?highlight=taurine

@wester130 said in Consensus on a good Vitamin C source?:

why not just acerola powder? it's 20% vitamin c,

Mind acerola when seeing 500 mg vit C in caps. Not only pure acerola, but often with additional powder. And then you're not sure of the appropriate one (without HM, the right degree 20.5 - 21.5° or the CAS reference).

@BearWithMe said in Safe laxative when taking blood thinners, diuretics and blood pressure medications?:

What would be the safest laxative

I'd take high dose (HD) vitamin C. For punctual problem. 1 g every hour (3x)
If not possible: HD magnesium + fibers from carrot salad with olive oil. You could add an apple to the salad. 2 carrots, one apple and 2 tbsp olive oil.
If recurrent, a prokinetic.

@Sunniva said in Bloodwork shows elevated TPOAb (Hashimoto's disease):

Recent Mercola interview and article on the subject.

You can print and download the pdf.

https://articles.mercola.com/sites/articles/archive/2025/01/12/excess-iodine-thyroid-health.aspx

1 Can't reach the interview: Must give your mail address.
2. Its claims excess iodine is bad (title). All excesses are bad.
3. Mercola sells iodine supplement, namely -/ 1500 mcg from kelp, I thinK.
He takes people for pigeons or something like that.
Conclusion: Vertical classification (trash can).

@nicemushroom17 said in Ears flushing:

What could cause my ears to flush and get really warm particularly in the evening? Shits annoying

Histamine, niacin type B3, wine, sulfur, ...

@Alomongerpete
LucH said in Consensus on a good Vitamin C source?:

Ok but the bioavailability (of most buffered vitamin C) is supposed to be somewhat less effective. But if you need a high level, like 1 g, and you suffer from acidity, it's acceptable.

See above for other details (answer to Mossy)

@Samyo

Samyo said
I wasnt eating much vitamin C prior to when my ferritin was at 488 on my first blood test.
=> Less beef (high in heme iron). When you eat meat, eat a slice of cheese (gouda or Leerdammer type). Above 40 mg Ca, there is less iron available, in theory.

Im finding goat milk to make me warm but very itchy and dandruff prone
=> What about a milk without lactose, at a moderate amount (180 ml)? If you tolerate it well (digestion), the problem is elsewhere. Similitude of protein configuration with whey (agglutinin wga)

grains/starch all lead to dry skin, when im hot my sweat stings my skin
=> Grain reaction is the sign of intolerance to gluten. Everybody is more or less reactive to wga. We repair the tight junctions during sleep. So moderation at the beginning of the process (SIBO) or total avoidance is required when the immune system has encoded the “enemy”.
=> Potatoes, bread and pasta are composed of two kind of starch. With soluble and insoluble fibers. If you don’t go to feces 2x/d, it remains too long in the second part of the colon. It feeds bacteria that have nothing to do there. Overgrowth in sight.

A lot of supplements have the same affect, drying to my skin, cascara, betaine hcl. I notice my left hand always drys out on my palm.
=> No betaine Hcl if irritable bowel.
No cascara too with irritable bowel. If you’re constipated, I’ll try another approach. Get informed on MMC + B1.
I’ve use Resolor 0.5 mg. to assist the MMC in order to re-educate/facilitate postprandial intestinal contractions (inter-digestive).
MMC = Migrant motor complex
MMC makes reference to the intestinal motility due to electrical contractions in the inter-digestive periods (between two meals).
See my forum for details (my log):
https://mirzoune-ciboulette.forumactif.org/t2029-demangeaison-et-histamine-journal-de-suivi-2?highlight=Complexe+moteur+migrant

Useful links
*) Dr. Costantini and bacterial overgrowth
SIBO, IBS, and Constipation: Unrecognized Thiamine Deficiency? – June 2020
https://www.hormonesmatter.com/sibo-ibs-constipation-thiamine-deficiency/
*) Thiamine Deficiency - A Potential Cause of SIBO and other Gut Dysfunction?
Elliot Overton – Nutrition and Functional Medicine – 01/2019
https://www.eonutrition.co.uk/post/thiamine-deficiency-a-major-cause-of-sibo
Thiamine deficiency - A consequence or cause of SIBO?
Thiamine Deficiency as Potential Cause for Gut Dysfunction.
· Gut motility, stomach acid and digestive enzyme secretion, and regulation of the intestinal barrier are governed by the vagus nerve, which is a component of the autonomic nervous system.
· The lower parts of the brain responsible for autonomic nervous system coordination are highly sensitive to thiamine deficiency.
· Thiamine deficiency can lead to autonomic nervous system dysfunction, abnormal vagal tone, and lower acetylcholine synthesis.
· Autonomic dysfunction can induce all of the symptoms associated with SIBO and should be considered in cases where traditional therapies are ineffective.

I took carrot salad to stop the direahh now, my bowels have stopped working
=> 30 to 40 g fibers when normalized bowels.
Need to calm down first. + reeducation of MMC.
If you suffer from bacterial overgrowth (gas, flatulence, alternate diarrhea with constipation, bad smell of stools (rotten eggs), you must elaborate a plan, with a progressive “attack”. First calm down, then moderate and orientate the kind of bacteria, possibly with some essential oils (e.g.) to kill excess proliferation. Don’t take a medicine / supplement to amplify the good microbiota at first side.

Info on Resolor (prucaloride 0.5 mg), acting as a prokinetic, not as a laxative.
Prokinetics have the capacity to amplify and coordinate muscular contractions of the intestine. They can act on different sites of action, both on the upper part of the digestive system such as the stomach or the small intestine and on the colon. Prokinetics can improve gastric emptying by coordinating the closing of the lower esophageal sphincter and the opening of the pyloric sphincter while the stomach contracts. They are known for their ability to stimulate the migrating motor complex (MMC) to clean the small intestine of this waste. Certain prokinetics have the ability to improve intestinal transit and can be used for example during constipation. However, prokinetics should not be confused with laxatives. (…)

@GRay said in B-complex and or Multi recommendation?:

I heard Georgi talking about it many times in a negative way as cancer promoter

Not at this dose, in a supplement, as an antioxidant (citric acid).
The dual role of citrate in cancer
Excerpt
In this context, targeting citrate and citrate-related metabolism [[6], [7], [8]] may appear to be a novel and hopeful option. Citrate is an intermediate of the tricarboxylic acid (TCA) cycle (also known as Krebs cycle). In the cytosol, it is cleaved by ATP-citrate lyase (ACLY) into oxalacetate (OAA) and acetyl-CoA. The latter is the primary substrate for fatty acid (FA) synthesis (FAS) or protein acetylation (either in the cytosol or in the nucleus for epigenetic modifications). Increased de novo FAS is one of the hallmarks of cancer cells, as well as an increase in aerobic glycolysis, the so-called Warburg effect [9]. Therefore, an adequate citrate supply is crucial to sustain cancer cells growth. However, citrate is also a Ca2+ and Mg2+ chelator, as well as a potent inhibitor of phosphofructokinase-1 (PFK1), the key regulatory enzyme of glycolysis [10], and also of phosphofructokinase-2 (PFK2) [11], which produces fructose-2,6-bisphosphate (F-2,6-BP), the main potent activator of PFK1 [12]. Consequently, proliferative cancer cells need to strictly control their intracellular citrate level to keep their metabolism balanced. Indeed, while a low level of citrate could impair cancer cell growth due to decreased FAS, an excessive level may have detrimental effects on glycolysis, ATP production and cell survival [13,14]. Therefore, such a need for a strict control of intracellular citrate level by cancer cells may offer two strategies potentially valid for cancer treatment, i.e., (1) reducing intracellular citrate levels (for example by inhibiting citrate uptake) and (2) flooding cells with excessive citrate to arrest glycolysis.
https://doi.org/10.1016/j.bbcan.2023.188987
Science Direct 2023. Philippe Icard et al.