H4K5 lactylation drives a positive feedback loop between inflammation and metabolic dysfunction in acute myocarditis by promoting macrophage pro-inflammatory transition and upregulating TNF/NF-κB signaling through Rap1 transcriptional activation.
Key Findings
Results
Acute myocarditis induced an increase in glycolysis and lactate accumulation in myocardial tissue.
Glycolytic reprogramming was identified as a key pathological feature of acute myocarditis
Lactate accumulation was observed as a downstream consequence of enhanced glycolysis
Immunometabolic reprogramming of macrophages was characterized as a central pathological mechanism
The findings establish a link between metabolic dysfunction and inflammatory pathology in acute myocarditis
Results
Inhibition of lactate production ameliorated myocardial injury in acute myocarditis.
Pharmacological or experimental inhibition of lactate production was used as an interventional strategy
Reduction in lactate levels corresponded with measurable improvement in myocardial injury markers
This finding supports a causal role for lactate in driving myocardial damage
Lactate inhibition also shifted macrophage phenotype from pro-inflammatory to anti-inflammatory subtype
Results
Lactate promoted a pro-inflammatory transition of macrophages, thereby amplifying the inflammatory response in acute myocarditis.
Lactate exposure drove macrophages toward a pro-inflammatory phenotype
Inhibition of lactate in macrophages shifted their phenotype from pro-inflammatory to anti-inflammatory
Macrophage immunometabolic reprogramming was identified as a key pathological feature of acute myocarditis
The lactate-macrophage axis was shown to amplify systemic cardiac inflammation
Results
A significant increase in H4K5 lactylation (H4K5la) was observed in macrophages during acute myocarditis.
H4K5la is a histone post-translational modification driven by lactate accumulation
This lactylation mark was specifically enriched in macrophages in the context of myocarditis
H4K5la levels were found to be lactate-dependent, linking metabolic state to epigenetic regulation
H4K5la was enriched at inflammatory pathway gene loci, suggesting a functional epigenetic role in driving inflammation
Results
H4K5la drove transcriptional expression of Rap1, which in turn upregulated TNF/NF-κB signaling.
H4K5la was identified as a transcriptional activator of the Rap1 gene in macrophages
Rap1 upregulation downstream of H4K5la activated the TNF/NF-κB signaling pathway
This pathway is a canonical driver of pro-inflammatory gene expression
The H4K5la–Rap1–TNF/NF-κB axis constituted a mechanistic link between lactate metabolism and inflammatory gene transcription
Results
Lactate-dependent H4K5la formed a positive feedback loop that amplified inflammation in acute myocarditis.
H4K5la was enriched at inflammatory pathway genes, reinforcing inflammatory transcription
Inflammation driven by NF-κB signaling in turn enhanced glycolysis and lactate production
This created a self-reinforcing cycle between metabolic dysfunction and inflammatory signaling
The positive feedback loop between H4K5la and inflammation was identified as a central pathomechanism of myocarditis progression
Results
Inhibition of Rap1 reduced cardiac inflammation, broke the positive feedback loop, lowered H4K5la levels, and delayed ventricular remodeling.
Rap1 inhibition was used as a therapeutic intervention in the experimental myocarditis model
Targeting Rap1 downstream of H4K5la was sufficient to interrupt the feedback loop between metabolism and inflammation
Rap1 inhibition resulted in decreased H4K5la levels, suggesting downstream feedback regulation of the epigenetic mark
Ventricular remodeling, a marker of disease progression toward cardiomyopathy, was delayed by Rap1 inhibition
These findings position Rap1 as a potential therapeutic target for inflammatory cardiomyopathy
What This Means
This research suggests that in acute myocarditis—a dangerous inflammation of the heart muscle—the heart's immune cells (macrophages) undergo a shift in how they produce energy, relying heavily on a process called glycolysis that generates large amounts of lactate (a metabolic byproduct). This lactate accumulation does not just reflect the disease; it actively makes it worse. The lactate chemically modifies a protein that packages DNA in the cell nucleus (a histone protein called H4K5), leaving a mark called 'lactylation.' This mark switches on genes that drive more inflammation, particularly through a molecule called Rap1 and a well-known inflammatory pathway called TNF/NF-κB, creating a vicious cycle where inflammation produces more lactate, which drives more inflammation.
The study also found that blocking lactate production reduced heart injury and changed macrophages from an inflammation-promoting type to a healing type. More importantly, blocking Rap1—a key node in this feedback loop—reduced heart inflammation, lowered the damaging H4K5 lactylation marks, and slowed the structural deterioration of the heart (ventricular remodeling) that can lead to heart failure.
This research suggests that the metabolic-epigenetic feedback loop centered on H4K5 lactylation and Rap1 plays a critical role in worsening acute myocarditis, and that targeting this loop—particularly by inhibiting Rap1 or reducing lactate—could represent a new therapeutic strategy for patients with inflammatory heart disease. This is meaningful because acute myocarditis currently has limited targeted treatments and can rapidly progress to life-threatening heart failure.
Zhao Y, Cai Y, Shen S, Wen Y, Li T, Kang L, et al.. (2026). H4K5 lactylation exacerbates acute myocarditis by driving a positive feedback loop between inflammation and metabolic dysfunction.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1896701