Lactate: The Most Misunderstood Molecule in Biology

For over two centuries, lactate has been misnamed, mischaracterized, and blamed for things it did not do. The real story is far more interesting and far more important.

Part I

A Name Born in a Dairy, a Reputation Built in a Laboratory

The story of lactate begins not in a muscle, not in a hospital and not in an athlete but in a jar of sour milk. In 1780, Carl Wilhelm Scheele, a Swedish pharmacist and one of the most prolific chemists of his era, isolated a previously unknown compound from curdled milk. He named it Mjölksyra, Swedish for “acid of milk.” The Latin root, lactis, meaning milk, gave us the name we use today: lactic acid.^[1]

Scheele never saw an athlete. He never measured a muscle. He found his molecule in a dairy product, and the name stuck for 245 years.

The next chapter of lactate’s story was written in a pathology suite. In 1843, the German physician-chemist Johann Joseph Scherer found lactic acid in human blood but only under pathological conditions, obtained during autopsy in cases of septic and hemorrhagic shock.^[2] The association was immediate and damning: lactic acid appeared in dying patients. Carl Folwarczny confirmed its presence in the blood of living patients in 1858, again in disease states, leukaemia and septicaemia.

So by the mid-19th century, without a single experiment in a healthy exercising human, lactic acid had already acquired its reputation. It was a molecule of sour milk and dying bodies. What remained was for science to cement that reputation formally and a Nobel Prize would do exactly that.

From Frog Legs to a Nobel Prize

Between 1918 and 1922, the German biochemist Otto Meyerhof conducted a series of experiments on isolated frog muscle. In controlled conditions, muscle preparations were electrically stimulated under low-oxygen conditions until fatigue. Meyerhof showed that glycogen breakdown was closely coupled to lactate production during contraction, without oxygen consumption. During recovery, in the presence of oxygen, a portion of the lactate was oxidized, and the energy released supported the resynthesis of the remaining lactate back into glycogen.^[3]

For this discovery of the fixed relationship between oxygen consumption and lactic acid metabolism in muscle, Meyerhof shared the 1922 Nobel Prize in Physiology or Medicine with the British physiologist A.V. Hill.

The problem was that the model was built on an artificially constructed system, a dead frog leg in a dish, that bore little resemblance to how lactate behaves in a living, breathing, intact organism.

Figure 1. Otto Meyerhof and schematic of his experimental calorimeter setup used to study isolated frog muscle under oxygen-deprived conditions, forming the basis of early interpretations of lactate production.

Lactate found its way into every textbook, every physiology course, every clinical training program, every coach’s vocabulary. When athletes felt the burn, it was lactic acid. When patients developed elevated lactate in the ICU, it signaled acidosis and lack of tissue oxygenation. The molecule’s identity was fixed: a waste product of anaerobic desperation, a marker of failure, a cause of fatigue.

That distinction would take another six decades to fully unravel, and it would take a runner from Queens to do it.

Part II

The 400-Meter Runner Who Swam Upstream

Dr. George A. Brooks grew up running. As a young intercollegiate athlete at Queens College in New York in the 1960s, he ran the 400m and was deeply interested in understanding his own performance. When he asked his coach why his times were not where he wanted them, the answer came back quickly: too much lactic acid, too much oxygen debt. Go read about it.

He did. He read Hill and Meyerhof. He read the Nobel Prize-winning science. And something about it did not sit right with him. The framework required that lactate was a problem, a toxic byproduct of oxygen-deprived muscle, a dead-end metabolite. But that did not match what he experienced or what he observed. Why would the body produce something in such large quantities, during the very activity it was designed to support, if it were purely a waste product?

That question became a career. George Brooks completed his doctorate in exercise physiology and joined the faculty at the University of California, Berkeley in 1971. From a modest laboratory in the basement of the campus gymnasium, he has spent more than five decades redefining lactate metabolism and advancing our understanding of cellular bioenergetics.

Figure 2. A young George Brooks running 400m at the Madison Square Garden in NYC.

Before describing what Brooks found, it is worth understanding the scientific lineage he was pushing against. The Kaiser Wilhelm Institute was the address where modern cellular bioenergetics was born. Otto Warburg, who received the Nobel Prize in 1931 for his work on cellular respiration and the respiratory enzyme, ran his laboratory there, and the Institute became the intellectual center of metabolic science for a generation. Meyerhof, influenced by Warburg’s framework of cellular respiration and oxidative metabolism while himself deep into the biochemistry of glycolysis, was also part of that environment. And Hans Krebs, Warburg’s direct mentee, went on to describe the tricarboxylic acid cycle (Kreb´s cycle), earning his own Nobel Prize in 1953.

Three Nobel Prizes, one intellectual lineage, all centered on the Kaiser Wilhelm Institute in Berlin. Warburg, Meyerhof mand Krebs each illuminated a portion of the pathway that lactate sits at the center of. They described glycolysis. They described the Krebs cycle. They mapped the machinery of cellular energy production with extraordinary precision. And yet lactate remained the unresolved piece in each of their frameworks. They got close, but the full picture would have to wait. Dr. Brooks did solve it…Stockholm has recognized lesser contributions.

Working from his laboratory at Berkeley, Brooks spent the 1980s studying lactate in living, intact organisms under real physiological conditions, not isolated tissue or oxygen-deprived preparations, but exercising animals and humans with intact circulation and functioning mitochondria. Using innovative isotopic tracer techniques, he was able to quantify lactate kinetics in vivo, including rates of appearance, disappearance, uptake, and production, fundamentally redefining lactate as a dynamic, circulating fuel rather than a metabolic dead end.

What he found overturned the paradigm completely. First, a correction of terminology: at physiological pH, the molecule exists almost entirely in its dissociated ionic form. The correct name is lactate, not lactic acid. Lactic acid essentially does not exist in the body at normal pH, a distinction that is not merely semantic but chemically meaningful.

Second, and far more consequential: lactate is produced continuously under fully aerobic conditions, not as a consequence of oxygen lack, but as an obligatory product of glycolysis. Normal, healthy, oxygen-rich cells produce lactate all the time. And crucially, other cells and tissues take it up and burn it as fuel. It was not going nowhere. It was going everywhere.

Brooks formalized this in the Lactate Shuttle Hypothesis,^[4] which has since become one of the most important frameworks in metabolic physiology, and which is no longer a hypothesis as it has been proven. Over the past 55 years, Brooks has continued extending and deepening this work producing one of the most consequential bodies of research in the history of physiology and cellular metabolism.

I had been studying Brooks’ papers as a student for years before I ever met him. At a bike race in California, I finally did. I remember feeling, despite being a grown professional with my own career, like a teenager meeting an idol. I could barely find my words. Since then, George has become a mentor, a colleague and a dear friend. For the past 15 years I have had the immense honor of working alongside him. Part of the work described below grew directly from that collaboration.

Part III

What Lactate Actually Is and Does: The Biochemistry

Glycolysis is the ten-step process by which glucose is broken down in the cytosol to produce lactate, pyruvate and ATP. At step six, NAD⁺ is reduced to NADH, and for glycolysis to keep running, that NADH must be reoxidized back to NAD⁺. If it is not, glycolysis stalls and ATP production stops.

This is where lactate becomes indispensable. The enzyme lactate dehydrogenase (LDH) converts pyruvate to lactate, and in doing so, simultaneously reoxidizes NADH back to NAD⁺. The reaction is: pyruvate + NADH + H⁺ → lactate + NAD⁺.

Note also what the LDH reaction does to protons: it consumes one H⁺ from the cytosol in the process of converting pyruvate to lactate. This is a mild but real buffering effect. Lactate does not cause acidosis, it modestly reduces it. And it simultaneously maintains the NAD⁺/NADH ratio, which is the cellular redox ratio, a key regulator of cellular homeostasis.

The acidosis that athletes experience during intense exercise comes from a different source: ATP hydrolysis. When ATP is broken down to ADP and inorganic phosphate to power muscle contraction, a proton is released: ATP → ADP + Pi + H⁺. The harder and faster the muscle works, the more ATP is hydrolyzed, and the more protons accumulate in the cytosol. pH falls and Lactate appears at the same time, which is why the association was made historically, but lactate was at the scene of the crime, not the criminal. It was actually trying to help.

When mitochondrial oxidative capacity is overwhelmed and lactate can no longer be cleared efficiently, the problem compounds. Protons from ATP hydrolysis accumulate in the cytosol alongside protons that lactate would normally carry into the mitochondria, but cannot, because the mitochondria are saturated. pH falls, impairing calcium release from the sarcoplasmic reticulum, inhibiting phosphofructokinase (the rate-limiting enzyme of glycolysis itself), and reducing both the force and velocity of muscle contraction. The muscle begins to shut itself down, a built-in emergency governor on runaway glycolysis.

But this is the pathological scenario. Under normal physiological conditions, lactate does not accumulate because mitochondria consume it.

Through MCT1 (monocarboxylate transporter 1), lactate enters the mitochondria, where it is converted back to pyruvate by mitochondrial LDH. Pyruvate is then converted to acetyl-CoA by the pyruvate dehydrogenase complex and enters the Krebs cycle, feeding the electron transport chain to produce ATP. Brooks’ laboratory characterized the mitochondrial lactate oxidation complex (mLOC), MCT1, mitochondrial LDH, and cytochrome oxidase sitting together on the inner mitochondrial membrane as an organized molecular machine specifically designed to oxidize lactate.^[5] This is not a loose sequence of reactions. The cell built dedicated infrastructure for it. That is not how you treat waste.

This is also the answer to the question Meyerhof raised but could not resolve a century ago: what happens to lactate in the presence of oxygen? The mechanism is now clear, down to the molecular level.

The broader significance of this goes beyond a single pathway. Lactate is produced continuously in virtually all glycolytic tissues, even at rest, not episodically, not only during hard exercise. It circulates continuously through the bloodstream and is taken up and oxidized by the heart, brain, working muscle, and kidneys at all times. In highly oxidative tissues it is not merely an acceptable fuel but a preferred one.

This preference matters because of a key asymmetry: blood glucose is tightly regulated and heavily buffered by hormonal systems, held within a narrow range regardless of what is happening metabolically. Blood lactate is not. Its concentration rises and falls freely in response to glycolytic activity, making it a sensitive, real-time signal of cellular metabolic flux that glucose cannot provide.

Figure 3. Lactate does not cause acidosis. Its formation regenerates NAD⁺ for the continuation of glycolysis and it consumes protons, helping buffer pH and sustain glycolysis, while acidosis primarily arises from ATP hydrolysis during high-energy demand.

Part IV

The Lactate Shuttle: A Universal Energy Distribution System

Beyond the intracellular pathway, Brooks described the cell-to-cell lactate shuttle, one of the most important concepts in modern physiology.^[4,5]

Fast-twitch (type II) muscle fibers are highly glycolytic and have relatively low mitochondrial density. They produce lactate rapidly during exercise and export it via MCT4 (monocarboxylate transporter 4) into the interstitium and bloodstream. Slow-twitch (type I) muscle fibers, which are rich in mitochondria, take up that lactate via MCT1, shuttle it into their mitochondria, and oxidize it as fuel. The same process occurs between working muscle and the heart, the brain, the kidneys, and other organs, all of which express MCT1 and have the mitochondrial machinery to consume lactate.

Lactate is a universal fuel. Any organ with mitochondria can use it, the heart, brain, kidneys, and working muscle all take up and oxidize lactate from the circulation based on concentration gradients and metabolic demand.

As mentioned above, when lactate enters mitochondria via MCT1, an H⁺/lactate symporter, it carries a proton with it. During active lactate clearance, protons that contribute to acidify the cytosol are co-transported into mitochondria. Lactate is therefore not just a fuel carrier, it actively participates in pH regulation, removing the very protons whose accumulation would impair muscle function.

This has a powerful practical implication. An athlete with excellent mitochondrial function clears lactate so efficiently that it barely appears in the blood even at high work rates. An athlete with poor mitochondrial function sees lactate rise rapidly because the production-clearance balance is tilted. Blood lactate at a standardized power output is therefore a direct readout of mitochondrial function, not a measure of anaerobic metabolism, not a marker of oxygen deficiency, but a quantitative index of the gap between glycolytic production and mitochondrial clearance capacity.

Consider two cyclists at 300 watts. Cyclist A has a blood lactate of 1.5-2 mmol/L, mitochondria are consuming lactate as fast as it is produced through both the intracellular and cell-to-cell shuttles, protons are being co-transported into mitochondria via MCT1, and the system is in equilibrium. This is zone 2, the point of maximum mitochondrial stress before the system becomes unsustainable. Cyclist B has a blood lactate of 7 mmol/L at the same power. Their mitochondrial capacity is significantly lower, the shuttles are overwhelmed, lactate escapes to the blood, protons accumulate in the cytosol, pH falls, and performance deteriorates. The difference between 1.5 and 7 mmol/L at identical power is not a difference in effort. It is a difference in mitochondrial function, and from that single number you can infer fitness, predict competition behavior, and design a training intervention.

This is the practical power of understanding lactate correctly. The deeper mechanistic detail, MCT expression, LDH isoforms, PDH regulation, substrate partitioning, will be covered in the next article in this series. For now, let us continue with the broader roles of lactate.

Figure 4. The lactate shuttle: lactate produced in glycolytic fibers is transported to oxidative fibers, where it is converted to pyruvate and used in the mitochondria to produce energy.

Figure 5. Performance is not defined by power alone, but by mitochondrial capacity. The same workload can reflect metabolic control or metabolic failure.

Part V

Lactate as a Lactormone and Exerkine: Signaling Beyond the Muscle

Lactate behaves as what Brooks has termed a lactormone, a molecule with hormone-like properties, functioning simultaneously as an endocrine, paracrine, and autocrine mediator.^[6,7] Its receptor-mediated effects span multiple organ systems and extend well beyond what any fuel molecule would be expected to do.

One of the clearest examples is the regulation of fat metabolism. During high-intensity exercise, the body must shift rapidly toward carbohydrate as its primary fuel, fatty acids simply cannot be oxidized fast enough to meet the ATP demand. Lactate facilitates this shift through two mechanisms. First, it binds to GPR81 (also known as HCAR1), an orphan G-protein-coupled receptor expressed in adipose tissue, and suppresses lipolysis, the breakdown of stored fat into circulating fatty acids.^[8] Second, as Brooks and I demonstrated in neonatal rat cardiomyocytes, lactate inhibits the activity of both CPT1 and CPT2, the enzymes responsible for transporting fatty acids across the inner mitochondrial membrane, significantly reducing the import of fatty acids into mitochondria for oxidation.^[9] Lactate is therefore acting as an endocrine signal (binding to receptors in adipose tissue) and as an autocrine mediator (acting locally within the cardiomyocyte) to redirect metabolism toward carbohydrate. It does not merely reflect the shift in fuel use, it actively orchestrates it.

Beyond fat metabolism, lactate functions as an exerkine, one of a class of signaling molecules released during exercise that exert beneficial effects on multiple organ systems.^[6,7] Exercise mobilizes dozens of these molecules simultaneously, and together they contribute to the systemic benefits of physical activity on metabolic health, immune function, cardiovascular fitness, and neurological health. Lactate is the major player among them.

In the brain, lactate from the circulation is taken up by astrocytes and neurons and serves both as fuel and as a signaling molecule. It stimulates the production of BDNF (brain-derived neurotrophic factor) which supports synaptic plasticity and neuroprotection. Lactate also promotes neurogenesis in the hippocampus and acutely improves executive function. This may be one of the most important molecular explanations for the well-established cognitive and mood-enhancing effects of aerobic exercise: the lactate produced during exercise is a direct signal to the brain that physical work is occurring, and the brain responds with neuroplastic adaptation.

Lactate also exerts epigenetic effects through a mechanism only recently discovered: histone lactylation. Zhang et al. demonstrated in 2019 that lactate can modify histone lysine residues, a post-translational modification that directly alters gene expression programs.^[10] Lactate does not just signal through receptors and transporters, it reaches inside the nucleus and changes which genes are transcribed. The implications are significant in both normal physiology and in disease, as the next section makes clear.

Figure 6. Lactate as a central metabolic signaling molecule, coordinating brain, muscle, cardiovascular, mitochondrial, and cellular functions across the body.

Part VI

Lactate in Cancer: The Lactagenesis Hypothesis

In the spring of 2016, I attended the American College of Sports Medicine annual meeting in Boston and found a moment to speak with George. I told him: “George, I think we can explain the Warburg effect.” He looked at me with calm, measured eyes and quiet curiosity. “What is it?” he asked. I said: “George — it’s lactate.”

By that point I had spent seven months developing a new hypothesis that I believed could explain what Warburg had observed almost a century earlier but never fully resolved: the systematic overproduction of lactate by cancer cells even in the presence of oxygen. I sent George a draft and asked him to help me take it to the finish line. What followed was one of the most intellectually rewarding experiences of my scientific life.

The paper was rejected eight times. All journals declined without review. Two responded with what I can only describe as barely concealed amusement at the idea. It was finally published in Carcinogenesis in 2017.^[11] Almost ten years later, it has over 800 citations. The work has contributed, I believe, to the renaissance of cancer metabolism research and to opening new doors for targeting the Warburg effect therapeutically.

Our argument was this: the Warburg effect, cancer cells producing large amounts of lactate even when oxygen is abundant, first observed by Warburg in 1923, is not a metabolic accident. It is purposeful. The cancer cell produces lactate for carcinogenesis. Lactate is the mechanism, not the byproduct. We called this the Lactagenesis Hypothesis.

With subsequent funding, we were able to begin testing this hypothesis experimentally. In a study of MCF7 human breast cancer cells, we demonstrated that lactate, both produced endogenously by the cells through aerobic glycolysis and supplied exogenously, significantly upregulated the transcriptional activity of key oncogenes, transcription factors including and cell cycle genes, while suppressing tumor suppressors.^[12] Lactate was not merely present in these cancer cells. It was regulating the genetic machinery of carcinogenesis. We proposed it as an oncometabolite, a metabolite capable of driving cancer formation through direct regulation of gene expression.

Subsequent work extended these findings. We showed in breast and lung cancer cells that lactate regulates the expression of genes involved in the epithelial-to-mesenchymal transition (EMT), the process by which cancer cells acquire the capacity for invasion and metastasis. When we silenced LDHA, the enzyme that produces lactate, we observed suppression of EGFR protein expression, one of the most important drivers of cell growth and proliferation in cancer, as well as suppression of HIF-1α.^[13] Inhibiting lactate production, in other words, could shut down key oncogenic pathways within 48 to 72 hours.

Lactate also drives carcinogenesis through histone lactylation, the epigenetic modification of histones described by Zhang et al. in 2019.^[10] Through lactylation, lactate directly alters gene expression programs in tumor cells in ways that promote survival, proliferation, and immune evasion. This is now recognized as a major mechanism in cancer biology.

Angiogenesis, the formation of new blood vessels to supply the growing tumor with glucose, is also directly regulated by lactate. Tumors require an expanding vascular network to sustain their metabolic demands, and lactate is one of the primary signals that drives this process. The tumor microenvironment, rich in lactate, becomes a niche that actively promotes its own expansion.

One the most clinically significant finding concerns the immune system. Under normal conditions, T cells patrol the body and destroy foreign or abnormal cells, including cancer cells. Cancer cells have evolved a counter-strategy: immune checkpoints. These are molecular brakes on T cell activity, ligands produced by cancer cells that bind to receptors on T cells and deactivate them before they can kill the tumor. It is a kryptonite effect, deployed by the cancer to neutralize its most dangerous predator.

The discovery that immune checkpoints could be blocked therapeutically led to immunotherapy, most notably pembrolizumab, a PD-1/PD-L1 inhibitor, and the 2018 Nobel Prize awarded to James Allison and Tasuku Honjo. It was a genuine revolution. But pembrolizumab alone works in a limited subset of cancers and has shown limited efficacy against most solid tumors. The reason may be that we have been focused on one checkpoint while tumors express many.

In our most recent work, we show that lactate is the major regulator of the expression of multiple immune checkpoints simultaneously, not just PD-L1, but CD80, CD73, LGALS9, CD47, VISTA, and others, in both breast and lung cancer cell lines.^[14] Different cancer cell lines showed strikingly different checkpoint patterns under chronic lactate-producing conditions, revealing a heterogeneous immune escape landscape driven by a shared upstream metabolic state: lactate accumulation. This suggests that the limited efficacy of single-checkpoint immunotherapy in many solid tumors may reflect the fact that we are blocking one road while the tumor has many. And lactate may be the upstream driver that keeps them all open.

Figure 7. Lactate is not a byproduct of cancer metabolism, it is a driver, orchestrating gene expression, immune suppression, and tumor progression.

Part VII

Exercise Lactate vs. Cancer Lactate: The Same Molecule, Two Completely Different Stories

At this point, a reasonable reader might ask an uncomfortable question: if lactate drives cancer, should people with cancer stop exercising? Does exercise-induced lactate make cancer worse?

The answer is emphatically no, and understanding why requires understanding the fundamental difference between the two contexts.

Exercise-induced lactate is transient, purposeful and cleared. It is produced by working muscle, serves as fuel throughout the body, acts as an exerkine with broad systemic benefits and returns to resting levels within minutes of stopping exercise. It does not accumulate in any tissue. The muscle that produces it is largely resistant to carcinogenesis. Exercise reduces cancer risk and is increasingly studied as a therapeutic adjunct in cancer treatment.

Cancer-derived lactate is the opposite: chronic, unrelenting and trapped. Cancer cells produce it 24/7 through continuous aerobic glycolysis, not to distribute energy, but as part of the carcinogenic program itself. It stays within the tumor microenvironment, which becomes profoundly acidic, suppressing immune surveillance, driving angiogenesis, promoting metastasis, and sustaining the epigenetic programs that keep the cancer growing. It never stops.

Key Distinction

Same molecule. Completely different source, duration, destination, and consequence. Exercise lactate is a tightly regulated, transient, beneficial metabolic event. Cancer lactate is a chronic, pathological hijacking of the same biochemistry, deployed for carcinogenesis rather than for health.

If anything, the relationship points in the opposite direction: the mitochondrial adaptations driven by regular aerobic exercise, greater oxidative capacity, enhanced lactate clearance, upregulated MCT1 expression, may represent a biological defense against the pathological lactate accumulation that characterizes cancer metabolism. The body that handles exercise lactate well is a body with robust mitochondrial function, efficient lactate clearance, and a metabolic environment that is inhospitable to the Warburg effect.

Exercise is not the enemy. It may be part of the solution.

Figure 8. Lactate is beneficial when transient and harmful when chronic, due to mitochondrial dysfunction, driving adaptation in exercise and carcinogenesis in cancer.

In Summary: The Most Misunderstood Molecule

Lactate was named after sour milk. Its medical reputation was built from dying patients and frog legs deprived of oxygen. A Nobel Prize cemented a model that was fundamentally incomplete. And for six decades, that model sat unchallenged in every physiology and medical textbook on earth.

What we know now is different in every dimension. Lactate is the obligatory product of glycolysis and the guardian of cellular NAD⁺ homeostasis. It is the body’s primary carbohydrate energy currency, distributed via molecular shuttles within and between cells. A mild cytosolic buffer, a lactormone with endocrine, paracrine, and autocrine properties, an exerkine communicating with the brain, the immune system and adipose tissue. An epigenetic regulator through histone lactylation. And in cancer, a major driver of carcinogenesis, regulating oncogenes, promoting angiogenesis, suppressing immunity, sustaining the tumor microenvironment.

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NOTE: The next article in this series will go deeper into the mechanistic details of the lactate shuttle, the mLOC, and the lactate kinetics that underlie metabolic profiling in clinical and athletic practice. For those who want the full scientific picture, that article is for you.

References

1. Scheele KW. Opuscula chemica et physica. Leipzig, 1788–1789. [Original isolation of lactic acid from sour milk, 1780.]

2. Kompanje EJO, Jansen TC, van der Hoven B, Bakker J. The first demonstration of lactic acid in human blood in shock by Johann Joseph Scherer (1814–1869) in January 1843. Intensive Care Medicine. 2007;33(11):1967–1971. doi:10.1007/s00134-007-0788-7. PMID 17661014.

3. Nobel Prize in Physiology or Medicine 1922. Otto Meyerhof: for his discovery of the fixed relationship between the consumption of oxygen and the metabolism of lactic acid in the muscle. NobelPrize.org.

4. Brooks GA. Lactate: glycolytic end product and oxidative substrate during sustained exercise in mammals — the “lactate shuttle.” Comparative Physiology and Biochemistry. 1985.

5. Brooks GA. The Science and Translation of Lactate Shuttle Theory. Cell Metabolism. 2018;27(4):757–785.

6. Brooks GA, Osmond AD, Arevalo JA, et al. Lactate as a major myokine and exerkine. Nature Reviews Endocrinology. 2022;18:712.

7. Brooks GA, Osmond AD, Arevalo JA, et al. Lactate as a myokine and exerkine: drivers and signals of physiology and metabolism. Journal of Applied Physiology. 2023;134:529–548.

8. Liu C, Wu J, Zhu J, et al. Lactate inhibits lipolysis in fat cells through activation of an orphan G-protein-coupled receptor, GPR81. Journal of Biological Chemistry. 2009;284(5):2811–2822.

9. San-Millán I, Sparagna GC, Chapman HL, et al. Chronic lactate exposure decreases mitochondrial function by inhibition of fatty acid uptake and cardiolipin alterations in neonatal rat cardiomyocytes. Frontiers in Nutrition. 2022;9:809485.

10. Zhang D, Tang Z, Huang H, et al. Metabolic regulation of gene expression by histone lactylation. Nature. 2019;574:575–580.

11. San-Millán I, Brooks GA. Reexamining cancer metabolism: lactate production for carcinogenesis could be the purpose and explanation of the Warburg Effect. Carcinogenesis. 2017;38(2):119–133.

12. San-Millán I, Julian CG, Matarazzo C, Martinez J, Brooks GA. Is lactate an oncometabolite? Evidence supporting a role for lactate in the regulation of transcriptional activity of cancer-related genes in MCF7 breast cancer cells. Frontiers in Oncology. 2020;9:1536.

13. San-Millán I, et al. Role of Lactate in the Regulation of Transcriptional Activity of Breast Cancer-Related Genes and Epithelial-to-Mesenchymal Transition Proteins: A Comparison of MCF7 and MDA-MB-231 Cancer Cell Lines. bioRxiv. 2023. doi:10.1101/2023.03.23.533060

14. San-Millán I, Martinez JL, Lueke Pickard S, Hirsch FR, Rivard C, Brooks GA. Lactate-driven heterogeneity of immune checkpoint expression in breast and lung. bioRxiv. 2026. doi:10.64898/2026.01.11.698903