Lactate: From a waste metabolic product to a regulator of innate immune memory

Lactate, which was once thought to be just a waste product of metabolism, has emerged as a central player in how our innate immune system remembers past infections. In a new study published in Cell on May 29, 2025, a multinational research team led by Mihai Netea and Athanasios Ziogas at Radboud University Medical Center has shown that lactate shapes long-term immune behavior through epigenetic reprogramming.

Innate immune processes can generate a distinct form of memory in myeloid cells, which is largely epigenetic. This phenomenon, first described about a decade ago by Netea and colleagues, is known as trained immunity. Unlike classical lymphocyte-based memory, trained immunity enables monocytes, traditionally considered short-lived and non-specific, to respond more robustly upon re-exposure to pathogens.

To investigate this phenomenon, the team used the Bacillus Calmette-Guérin (BCG) vaccine, a 100-year-old vaccine originally developed to protect against tuberculosis. Beyond its protective effects against tuberculosis, BCG has been shown to enhance the immune system’s readiness to fight off a variety of unrelated infections, making it an established model for studying trained immunity.

Zooming in on this mechanism, the study identified histone H3 lactylation at lysine 18 (H3K18la) as a hallmark of trained immunity. This epigenetic mark was enriched at active enhancer regions of immune genes and persisted for at least three months after vaccination. Importantly, both genetic variation and pharmacological inhibition of lactate dehydrogenase (LDH) and p300, the enzyme that produces lactate and mediates lactylation respectively, significantly impaired this immune memory effect.

In the cover illustration of a recent issue of Cell, the authors represented trained immunity by showing a monocyte with a cord-like motif, symbolizing the boosted responsiveness characteristic of this process, while the background subtly evokes the lasting epigenetic memory driven by lactylation.

Next steps: from molecular mechanisms to prevention and therapy

Trained immunity is increasingly recognized not only for its role in enhancing vaccine responses, but also for its contribution to chronic inflammation in diseases like atherosclerosis or autoinflammatory disease. Understanding how metabolites and epigenetics intersect may allow researchers and clinicians to fine-tune immune responses. This could mean enhancing beneficial immune memory in vaccines, or dampening it when it turns maladaptive.

This research is part of Radboudumc Research Program: Innate immunity in health and disease

Read the study here

Ziogas A, Novakovic B, Ventriglia L, Galang N, Tran KA, Li W, Matzaraki V, van Unen N, Schlüter T, Ferreira AV, Moorlag SJCFM, Koeken VACM, Moyo M, Li X, Baltissen MPA, Martens JHA, Li Y, Divangahi M, Joosten LAB, Mhlanga MM, Netea MG. Long-term histone lactylation connects metabolic and epigenetic rewiring in innate immune memory. Cell. 2025 May 29;188(11):2992-3012.e16. doi: 10.1016/j.cell.2025.03.048. Epub 2025 May 2. PMID: 40318634