Another weak spot of cancer cells: ATP citrate lyase inhibition

ATP citrate lyase is an important enzyme for he fast dividing cancer cells

ATP citrate lyase (ACL or ACLY) is an intracellular enzyme (located in cytosol) responsible for the conversion of citrate that comes out of the mitochondria,  to acetyl-CoA and oxaloacetate.

ATP citrate lyase is primarily expressed in lipogenic tissues. Other vegetative tissues express little to no levels of the enzyme. However, it has been it discovered that the fast growing cancer cells are characterized by a high level of ATP citrate lyase activity. (Ref.)

Some are even suggesting that high level of acetyl-CoA required for cellular growth is what activates glycolysis and increased mitochondrial production of citrate, and the activity of ATP citrate lyase.

Indeed, in cancer cells the energy supply is produced mainly by the glycolysis of glucose, and part of the glycolytically derived pyruvate enters the truncated tricarboxylic acid cycle (TCA cycle, also known as citric acid cycle) in the mitochondria, where citrate is exported to cytosol via the tricarboxylate transporter. In the cytosol,  ACLY enzyme coverts citrate in acetyl-CoA (and oxaloacetate) which is very much needed by the fast growing cells to e.g. maintain an active chromatin structure through histone acetylation, and to produce specialized lipids much needed for various intracellular processes. In other words, ACLY is the enzyme that links glycolysis to fatty acid/lipid synthesis.

If acetyl-CoA is important for the cancer cells and if ACLY is the enzyme that converts acetyl-CoA, one expected effect is that if we inhibit ACLY, there will be a build-up of citrate in the cytosol , which in turn will lead to:
1. a reduction of acetyl-CoA available of the fast growing cancer cells
2. a build-up of citrate in cytosol that can act as a negative regulator of the glycolytic pathway, i.e. suppressing the consumption of glucose and thus the energy production. This is because Citrate down regulates glycolisis since it is an inhibitor of phosphofructokinase (PFK), the 2nd key enzyme of glycolysis pathway (Ref.).

ATP citrate lyase inhibitors: Hydroxycitrate (HCA) one of the most accessible inhibitors

garcinia-cambogiaIndeed, here is a patent that proposed ACLY inhibition as a method for killing cancer, specifically the highly glycolitic ones

And here is an article discussing ACLY (or ACL which is the same) inhibitors (Ref)

One of the most known inhibitors of ACLY is Hydroxycitrate (HCA) which is derived from fruit rinds of Garcinia species including  Garcinia cambogia, Garcinia indica. HCA is a widely available supplement, e.g. Currently HCA is used as a supplement for weight loss.

Another ACLY inhibitor is Bempedoic acid (ETC-1002), currently (2017) in clinical trials investigated as a potential drug to reduce reduced LDL-C in patients who cannot tolarate statins (Ref.). The drug is investigated by Esperion Therapeutics Inc., a late-stage pharmaceutical company.

ACLY inhibition with HCA: Promising results in Human

One of the first group of doctors and scientist applying this concept in humans is prof Laurent Schwartz and coleagues in France (Association Cancer & Metabolisme). Following the screening of various drugs they came up with HCA & Alpha Lipoic Acid (ALA) as one of the best combinations to kill cancer and patented this (Ref.) under the name METABLOC.

I think this combination of HCA and ALA makes sense since ALA will redirect pyruvate towards the mitochondria (in a way similar to Dichloroacetate (DCA) – the mechanism will be discussed another time) which will finally go out of mitochondria as citrate and HCA will inhibit the conversion of citrate to acetyl-CoA that will lead to the accumulation of citrate in cytosol and down regulation of glycolisis. (An idea: on this line, it may be good to add citrate as a suppliment next to HCA and ALA to possibly increase the cellular citrate?). Citrate down regulates glycolisis since citrate is an inhibitor of phosphofructokinase (PFK), the 2nd key enzyme of glycolysis pathway (Ref.).

Bellow are some of the published articles after applying this concept on humans.

New Cancer Paradigm and New Treatment: The Example of METABLOC

Metabolic cancer treatment: Intermediate results of a clinical study

Administration and Side effects

Dose: In most of the clinical trials they used HCA (The minimum dose of HCA was 1.2 g/day and the maximum dose was 3 g/day) in combination with Alpha Lipoic Acid (The minimum oral dose of α-LA administered was 0.4 g/day, and the maximum dose was 1.8 g/day.) Example of HCA source is Super CitriMax

Side effects: Some patients had side effects such as stomach pain which disappeared on using proton pump inhibitors or by reducing the dose. According to various publications HCA is safe in humans at 5g/day with no specific toxicity. (Ref) The dose seems to be safe in humans up to 13.5g/day (Ref)

Ideas to improve the treatment protocol:

One ideas is to add Citrate supplements due to the reasons discussed above.

Another idea is to add DCA (Dichloroacetate) since DCA acts in a similar way as ALA while it may be more effective in reaching the cell.

Both Citrate and DCA are know as having anti cancer effects alone.

Yet another idea discussed in the patent (Ref.) is to use a tricarboxylate transporter inhibitor (such as Oxaloacetate). The tricarboxylate transporter is responsible for exporting citrate from the mitochondria down the concentration gradient to the cytosol. It’s inhibition would lead to accumulation of citrate into the mitochondria.

Update: 10-April-2017: when ACLYL is inhibited by HCA, tumor cells will express ACSS2 enzyme to convert acetate into the actyl-CoA (Ref.). ACSS2 level is modulated by SREBP2 (Ref.) and SREBP2 in turn can be modulated by Vitamin E derivatives (tocotrienols) (Ref.)

  • Dose: not yet sure what would be the best dose
  • Source: Online available supplements such as this one.
    Note: Thank you to Frank Liu for heads up on this point via his comment.


In the clinical trials using HCA some people saw tumor reduction and after some time it cam back. In that case, the escape mechanism may be explained by the following If that is the case, addition of ACSS2 inhibitor will solve the issue. I already passed over this idea to the relevant scientists and doctors in the field. 😉


With the above in mind, and given its safety profile, accessibility and low cost, I would add HCA to any anti cancer treatment protocol.


This site is not designed to and does not provide medical advice, professional diagnosis, opinion, treatment or services to you or to any other individual. Through this site and linkages to other sites, I provide general information for educational purposes only. The information provided in this site, or through linkages to other sites, is not a substitute for medical or professional care, and you should not use the information in place of a visit, call consultation or the advice of your physician or other healthcare provider. I am not liable or responsible for any advice, course of treatment, diagnosis or any other information, services or product you obtain through this site. This is just my own personal opinion regarding what we have learned on this road.

Related Articles

Leave a Reply

35 Comments on "Another weak spot of cancer cells: ATP citrate lyase inhibition"

Notify of
Dear Daniel, Really you are amazing.Where did you find those lots of valuable,cheap,effective combinations?You worked too much as i see. I like the the article that you linked(In every article we see the importance of combinations). We began HCA(1000mgxday, but %50 HCA written on box?) yesterday near DCA+others+chemo. But i am not sure about adding citric acid to our protocol.As we talked before DCA also may rise the citric acid accumulation. I wonder that if more citric acid more benefit?,but with higher HCA?( What should be the dosage of HCA after adding DCA+citric acid)? A hard question to answer i… Read more »
Daniel, I’ve researched the role of glutamine a little bit and found that glutamine can be the result of MYC, or the result of autophagy of cells. The glutamine is then converted to glutamate by Glutaminase, and further converted into a-Ketogluterate and pushed into the Krebs cycle by aminotransferase or GLUD1 where it can be used to generate ATP. This image explains the process, and I’m sure you understand it already. My thought is that maybe combining Chloroquine (which is illustrated to block the autophagy pathway in the image), along with DCA/Metformin to disrupt glucose metabolism along with intra-mitochondrial processes,… Read more »

Or chloroquine may be rendered unnecessary by inhibiting one of the later processes like TA/GLUD1 or Glutaminase.

Hi Meech, Thank you for sharing your idea. They said 2 drugs(HCA+ALA)is not enough and only slows the tumor growth,so you have to put 3th drug near them to shrink tumors. And they works for limited time and i am always thinking about it. My idea is like this:If we want a cure,we have to fight with everything,because they all works for limited time. Half knowledge is the most dangerous thing in cancer treatment,like what i am trying to do at this time. Yes i belive metabolic treatment of cancer BUT when my mother was diagnosed with peritoneal ovca,we never… Read more »
It’s a highly frustrating disease with many escape mechanisms and many ways to avoid being killed. It’s highly adaptive and that ends up being very frustrating since like you said, treatments may only work for a period and cease to work once the cancerous cells figure out another method by which to survive. The diagnoses are not always crystal clear as well. I know cancers where primary tumours can’t be found happen with some regularity. Important to note that I ceased citric acid treatment after maybe two to three months due to stomach upset. For me, it’s difficult to even… Read more »

Thank you very much Meech,
You are almost right,we tried lots of things to kill cancer cells without chemo.But didnt have any success without chemo.
Now it looks like chemo also donesnt work.Citric acid+HCA is my last hope.May be it totally blocks the fuel with others.A hope.


Dear Daniel,
You are very right.We use toxic chemo despite knowing not very effective after some time.
And loosing too many healthy cells.
We are loosing opportunity,time without using salinomycin,Phlorizin etc.,if we will go with chemo as you mentioned me before.
Kind Regards

Dear ergin, i don’t think i have much to contribute with sadly. I am deeply sad to see i am not the only one fighting but also happy i am not alone and maybe together we can succeed. After months of research on the internet, the only thing that promisses to kill resistant cancer cells is Paw Paw capsules / Graviola. I must say, me and my mother have tried it with a 1 month hardcore protocol. 3X2Capsules of Paw Paw and 10g Graviola Powder Tea every 4 hours. The resulting blood tests were very encouraging at first just after… Read more »

Thank you Alex,i ll write you tonight

Frank Liu

ATP-citrate lyase controls a glucose-to-acetate metabolic switch.

Frank Liu

Tumor cell metabolism: cancer’s Achilles’ heel.

Cancer as a mitochondrial metabolic disease.

A global view of the biochemical pathways involved in the regulation of the metabolism of cancer cells.


Hi Daniel, about your last update After Frank Liu remark:
You have a more recent research pub with an other simpler treatment:
Apigenin attenuate SREBP-2

For dosage it is simply a spoon of fresh parsel by day !

Have you contacted dr SCHWARTZ from France ?
If yes I will contact him for correcting.


The motto of Dr. SCHWARTZ:
a simple and non-toxic treatment


Dear Daniel.
Something of possible relevance with regards to hormones and HCA.
I’m not certain of what that means but it may prove of value.
Many thanks.