Introduction: Linking Cellular Metabolism to Innate Immune Memory

Innate immune cells can develop a form of long-lasting memory known as trained immunity, enabling them to mount stronger and more sustained responses to subsequent challenges. This phenomenon can be induced by microbial components or vaccines such as Bacillus Calmette–Guérin (BCG), providing broad, non-specific protection against diverse pathogens.

A defining feature of trained innate immune cells is profound metabolic reprogramming. Increased glucose consumption and aerobic glycolysis drive enhanced conversion of pyruvate into lactate. Once considered primarily a metabolic waste product, lactate is now recognized as a signaling metabolite capable of influencing gene regulation through histone lactylation, a post-translational modification that links cellular metabolism to chromatin regulation.

However, how lactate production and histone lactylation contribute to the establishment and maintenance of trained immunity has remained incompletely understood.

Comprehensive analysis of metabolic and epigenetic changes, together with reliable detection of histone lactylation, provides an important approach for addressing this question and understanding how transient metabolic changes can generate persistent immune memory.

Research Discovery: Histone Lactylation Connects Metabolic and Epigenetic Reprogramming

A landmark study published in Cell, titled “Long-term histone lactylation connects metabolic and epigenetic rewiring in innate immune memory”, led by Mihai G. Netea and Athanasios Ziogas at Radboud University, investigated the role of lactate and histone lactylation in BCG-induced trained immunity.

The study established a functional connection between increased lactate production, histone lactylation, and long-term innate immune memory.

Following BCG vaccination, monocytes and macrophages exhibited enhanced glycolytic activity and increased lactate production. Importantly, lactate release was positively associated with the production of inflammatory cytokines, including IL-1β and IL-6, suggesting a sustained relationship between lactate metabolism and trained immune responses.

At the chromatin level, BCG training induced persistent histone lysine lactylation, with H3K18la emerging as a prominent epigenetic mark. In contrast, LPS-induced tolerant macrophages did not show the same increase in global histone lactylation.

Genome-wide profiling further revealed that H3K18la was enriched at open chromatin regions, including active enhancers and promoters, and its enrichment correlated with gene expression. Notably, H3K18la marks associated with inflammatory genes such as IL1B persisted for days after the initial stimulus, providing evidence that histone lactylation may contribute to the epigenetic memory underlying trained immunity.

The study further identified p300/CBP as important regulators of H3K18la deposition and demonstrated that inhibiting lactate production or p300/CBP activity impaired trained immune responses.

Together, these findings establish histone lactylation as an important molecular interface between metabolic rewiring and long-lasting epigenetic regulation in innate immune memory.

PTM BIO Technology Contribution: Enabling Precise Detection of Histone Lactylation

Addressing Key Technical Challenges

Characterizing histone lactylation requires reliable tools capable of distinguishing lactylated proteins and, critically, specific modification sites. Because post-translational modifications can occur dynamically and at multiple lysine residues, accurate detection is essential for connecting changes in metabolic state with specific chromatin events.

In this study, PTM BIO provided lactylation pan-antibodies and site-specific histone modification antibodies, supporting the experimental validation of lactylation changes associated with trained immunity.

The combination of pan-lactylation detection and site-specific analysis enabled researchers to examine histone lactylation at both the global and individual-site levels.

Lactylation Antibodies Enable Critical Epigenetic Validation

Using lactylation pan-antibodies and the H3K18la site-specific antibody, the researchers demonstrated that BCG training markedly increased histone lysine lactylation in macrophages.

Among the modifications examined, H3K18la showed a particularly pronounced and sustained increase following BCG training. Pharmacological inhibition of lactate dehydrogenase or glycolysis reduced H3K18la levels, directly connecting cellular lactate metabolism with the accumulation of this histone modification.

This antibody-based validation was critical for establishing H3K18la as more than a correlated epigenetic feature. The persistence of H3K18la after the initial stimulus, together with its association with inflammatory regulatory elements, supported a model in which lactate-derived signals are translated into chromatin-level information.

From Modification Detection to Biological Mechanism

The study integrated histone lactylation profiling with ChIP-seq, RNA-seq, metabolic perturbation, and functional experiments to define the biological consequences of H3K18la.

H3K18la was preferentially associated with open chromatin and active regulatory regions. Its enrichment at inflammatory genes, including IL1B, was maintained during the trained state and correlated with transcriptional activity.

The researchers further demonstrated that inhibition of p300/CBP reduced H3K18la enrichment, highlighting the role of these acetyltransferase-related enzymes in regulating the lactylation landscape.

Together, these findings illustrate how precise post-translational modification detection, combined with genome-wide epigenomic and transcriptomic analyses, can help bridge the gap between metabolic changes and long-term gene regulation.

Scientific Impact: Establishing Lactylation as a Molecular Memory Mark

This study provides important evidence that metabolic reprogramming can influence long-term immune function through epigenetic mechanisms.

Rather than functioning solely as a byproduct of enhanced glycolysis, lactate can act as an epigenetic signal through histone lactylation, connecting cellular metabolism with chromatin regulation. The persistent H3K18la landscape provides a potential molecular explanation for how transient immune stimulation can produce durable changes in gene expression.

The findings also extend the biological significance of lactylation beyond individual cellular responses, placing it within the broader framework of innate immune memory and immunometabolism.

By linking lactate metabolism, H3K18la, chromatin regulation, and inflammatory gene expression, the study provides a foundation for exploring lactylation-related pathways in vaccine-induced trained immunity and inflammatory disease.

The work may also inform future strategies aimed at modulating trained immunity by targeting metabolic enzymes or regulators of histone lactylation, including LDH and p300/CBP.

PTM BIO: Empowering Next-Generation Post-translational Modification Research

The biological functions of emerging post-translational modifications depend heavily on the ability to detect and validate modification events with high specificity.

PTM BIO provides integrated solutions for post-translational modification research, including lactylation antibody technologies designed to support the characterization of metabolic-epigenetic signaling pathways.

Its lactylation antibody portfolio includes L-lactylation and D-lactylation pan-antibodies, enabling researchers to investigate distinct lactylation signals with greater specificity. Site-specific lactylation antibodies can further support the validation of individual modification sites and their functional relevance.

PTM BIO's research workflow can support projects across multiple stages:

Modification Screening → PTM Profiling → Site-specific Validation → Functional Characterization → Epigenetic Mechanism Exploration

By combining PTM Proteomics, antibody-based validation, bioinformatics, and downstream epigenomic approaches such as CUT&Tag, PTM BIO supports researchers in moving from modification discovery to biological mechanism.

PTM BIO is committed to empowering researchers with advanced PTM technologies and scientific solutions to uncover how metabolic signals reshape cellular function and drive complex biological processes.