A new layer of epigenetic regulation
Epigenetics is the study of heritable changes in gene expression that do not involve changes to DNA sequence itself. The canonical modifications include methylation of cytosine residues in DNA, and dozens of post-translational modifications to histone proteins — acetylation, methylation, phosphorylation, ubiquitylation, and more. Each modification alters the accessibility of chromatin and the binding affinity of transcriptional machinery.
In 2019, Zhao and colleagues published a paper in Nature describing a previously unknown histone modification: lactylation. They showed that L-lactate — the end product of anaerobic glycolysis and the molecule historically dismissed as a metabolic waste product — can directly modify lysine residues on histone proteins. The modification they characterised most carefully was H3K18la: the lactylation of lysine 18 on histone H3. But the team identified 28 sites of histone lactylation in total, distributed across H3 and H4 in particular.
This was a significant finding. It meant that the cell’s metabolic state — specifically, how much lactate it is producing — is directly communicated to the genome as an epigenetic mark. The chromatin switch between oxidative metabolism and anaerobic glycolysis is not merely a physiological state; it is inscribed in chromatin.
The Warburg effect and why lactate levels matter
To understand the significance of lactylation, it helps to know the Warburg effect. In the 1920s, Otto Warburg observed that cancer cells consume glucose at unusually high rates and convert it to lactate even in the presence of sufficient oxygen — a phenomenon he called aerobic glycolysis. Normal cells, when oxygen is available, primarily oxidise pyruvate in the mitochondria via the TCA cycle and oxidative phosphorylation, generating much more ATP per glucose molecule. Cancer cells short-circuit this by using lactate dehydrogenase A (LDHA) to convert pyruvate to lactate even in normoxia.
The Warburg effect was puzzling for decades. Why would a cell deliberately use the less efficient energy pathway? Answers have accumulated: glycolysis is faster, it provides biosynthetic precursors (ribose for nucleotides, glycerol for lipids, serine for one-carbon metabolism), and it generates NADPH needed to maintain the antioxidant pool. But the lactylation discovery adds another dimension. By elevating intracellular lactate, the Warburg effect also changes the epigenetic landscape — and H3K18la specifically drives genes associated with homeostatic response and certain reparative processes.
This creates a loop. A cell adopting aerobic glycolysis generates lactate, which lactylates histones, which alters the transcriptional programme, which may reinforce or modulate the glycolytic phenotype itself.
LDHA, LDHB, and the directionality of lactate metabolism
Lactate dehydrogenase exists as a tetrameric enzyme with two subunit types: LDHA (also called LDH-M for muscle) and LDHB (LDH-H for heart). Their tetrameric combinations produce five isoforms (LDH-1 through LDH-5) with distinct kinetic properties. The directionality is crucial. LDHA-rich isoforms preferentially convert pyruvate to lactate (the reduction direction), while LDHB-rich isoforms preferentially convert lactate back to pyruvate (the oxidation direction).
Cancer cells typically overexpress LDHA — this drives the Warburg effect by keeping pyruvate flowing into lactate rather than into the mitochondria. LDHB expression is often suppressed in cancer, reducing the cell’s capacity to oxidise lactate. The net result is high intracellular lactate, which — by the Zhao et al. mechanism — means high H3K18la marking.
LDHA inhibition is therefore a target of interest in oncology. Several LDHA inhibitors have been investigated. The question for spirulina researchers is whether any of spirulina’s components have meaningful LDHA inhibitory activity.
Phycocyanin and glycolytic flux
Phycocyanin, the dominant pigment protein in spirulina, has been studied for its effects on cellular energy metabolism and inflammatory signalling. Several studies have examined phycocyanin’s effects in cancer cell lines and found it reduces glycolytic flux — measured as lactate production rate or oxygen consumption ratio via Seahorse metabolic analysis.
The mechanism appears to involve multiple nodes. Phycocyanobilin, the chromophore of phycocyanin, inhibits NADPH oxidase (NOX) enzyme activity. NOX inhibition reduces reactive oxygen species (ROS) production. Elevated ROS in cancer cells normally stabilises HIF-1α (hypoxia-inducible factor 1-alpha) even under normoxic conditions — a process sometimes called pseudohypoxia. HIF-1α transcriptionally upregulates glycolytic enzymes including LDHA, aldolase, and enolase. By reducing ROS, phycocyanobilin destabilises HIF-1α, which in turn reduces the transcriptional drive on the glycolytic programme.
There are also more direct effects. A 2017 study in Oncotarget by Jiang and colleagues examining phycocyanin in hepatocellular carcinoma cells found reduced LDHA protein expression and reduced lactate output alongside reduced tumour growth in xenograft models. The LDHA reduction was associated with reduced NF-κB activity, and NF-κB is a known transcriptional activator of LDHA.
H3K18la specifically: what this mark does
Zhao et al. characterised the functional consequences of H3K18la using chromatin immunoprecipitation sequencing (ChIP-seq) in mouse bone marrow-derived macrophages treated with lipopolysaccharide (LPS) — a standard model of inflammatory activation. H3K18la marks accumulated at the promoters of genes associated with homeostatic functions in late-stage macrophage activation: arginase-1 (Arg1), vascular endothelial growth factor (VEGF), and transforming growth factor beta (TGF-β) among others.
This was interpreted as the chromatin mechanism by which macrophages transition from a highly inflammatory (M1-like) to a reparative and anti-inflammatory (M2-like) state. The late-stage elevation of lactate — after the initial glucose burst of inflammatory activation — drives H3K18la accumulation, which biases the transcriptome toward resolution rather than continued inflammation.
The implications here are somewhat counterintuitive. If H3K18la promotes resolution of inflammation, then some degree of lactate signalling is functionally important. The relevant question is not simply “is lactylation bad” but rather whether lactylation is occurring in the right context, at the right time, in the right cell types. The pathological form is sustained Warburg-type metabolism in cancer cells, where chronically high lactate and H3K18la may lock cells into a survival programme. In normal physiology, transient lactylation after inflammatory activation appears to serve resolution.
Alpha-ketoglutarate, TET enzymes, and the metabolite-epigenome axis
Lactylation is not the only example of a metabolite functioning as a direct epigenetic modifier. The broader field of metabolic epigenomics has established that TCA cycle intermediates profoundly influence the chromatin landscape. Alpha-ketoglutarate (also called 2-oxoglutarate) is a cofactor for TET enzymes — the dioxygenases that oxidise 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), the first step in active DNA demethylation. TET enzymes are also 2-oxoglutarate-dependent dioxygenases, and their activity is therefore directly coupled to mitochondrial TCA cycle flux.
When cells operate primarily via glycolysis (the Warburg phenotype), TCA cycle intermediates including alpha-ketoglutarate are depleted. This reduces TET enzyme activity, leading to DNA hypermethylation — which is a recognised feature of many cancers, often silencing tumour suppressor genes. The metabolic switch to aerobic glycolysis therefore has consequences not just for histone lactylation but for DNA methylation patterns too. These two mechanisms — H3K18la accumulation and TET-dependent demethylation impairment — work in the same direction: stabilising the transcriptional programme of proliferating cells.
Spirulina’s potential relevance here connects to its effects on mitochondrial function. Several studies suggest phycocyanin improves mitochondrial biogenesis markers including PGC-1α expression and promotes oxidative metabolism. If phycocyanin pushes cells toward oxidative phosphorylation and away from anaerobic glycolysis, it would be expected to raise alpha-ketoglutarate availability, support TET activity, and maintain appropriate DNA methylation patterns — while simultaneously reducing the lactate supply for pathological H3K18la accumulation.
Inflammation, macrophage polarisation, and lactylation
The macrophage polarisation literature provides a useful lens for thinking about how spirulina might interact with the lactylation pathway in inflammatory contexts. As noted above, H3K18la promotes M2-like polarisation via gene activation in late-stage macrophage responses. But inflammatory macrophages also undergo a dramatic metabolic switch — the M1 inflammatory state is accompanied by broken TCA cycle flux (the “broken Krebs cycle” described by O’Neill and colleagues), accumulation of succinate and itaconate, and increased glycolytic rate.
Phycocyanin has well-documented effects on macrophage inflammatory responses — reducing NF-κB activation, lowering IL-6 and TNF-α output, and in some studies shifting macrophage phenotype toward anti-inflammatory markers. The mechanistic bridge to lactylation is speculative at present but follows logically: by reducing the inflammatory activation that drives glycolytic switching in macrophages, phycocyanin may modulate the temporal dynamics of lactate accumulation and therefore H3K18la patterning.
Direct studies testing phycocyanin’s effect on histone lactylation have not yet been published, as of available literature. The Zhao et al. lactylation paper is relatively recent, and the downstream research has focused on characterising the writers, erasers, and readers of lactylation marks — the enzymatic machinery that adds and removes the modification, and the proteins that bind to lactylated histones. This machinery is now being investigated as a drug target. Spirulina’s position in this space remains at the mechanistic hypothesis stage.
What this means in practice
The lactylation story illustrates a broader principle: metabolism and gene expression are not separate systems. The metabolic state of a cell is continuously written into chromatin through modifications like H3K18la, acetylation (which uses acetyl-CoA), methylation (which uses SAM, dependent on one-carbon metabolism), and others. Dietary interventions that shift metabolic flux — including spirulina — therefore have the potential to influence epigenetic patterns indirectly, even without any direct interaction with chromatin-modifying enzymes.
The implications are most clearly relevant in contexts where aberrant metabolic reprogramming is the disease mechanism: cancer, chronic inflammatory conditions, and metabolic syndrome. In each of these, the Warburg-like glycolytic shift that elevates lactate and distorts the epigenome is part of the pathophysiology. Whether spirulina’s effects on glycolytic flux are large enough and specific enough to influence this at clinically meaningful levels in humans is genuinely unknown.
What the lactylation research has done is provide a new conceptual framework — one in which a metabolite historically dismissed as a waste product turns out to be a chromatin signal. Spirulina’s phycocyanin modulates glycolytic flux and lactate production in directions that are mechanistically interesting. The direct evidence remains at the cell and animal level. Human epigenomic studies examining spirulina’s effects on histone modification patterns have not been published. That is an honest assessment of where the field stands.