Pseudomonas hijacks lactate to rewire host defense

Few microbes are as adept at exploiting host vulnerabilities as Pseudomonas aeruginosa. In chronic respiratory diseases, such as cystic fibrosis, bronchiectasis, and chronic obstructive pulmonary disease (COPD), this opportunistic pathogen transforms the airway into a persistent niche with its extraordinary adaptability and capacity for antimicrobial resistance.1 While decades of work have elucidated host immune and epithelial responses to P aeruginosa, eradication remains elusive and recurrent infection often leads to accelerated disease progression and worse outcomes.2,3 What continues to make P aeruginosa so successful? The answer may lie not only in its arsenal of toxins and virulence factors but also in its capacity to hijack the very metabolic and epigenetic networks that underpin airway epithelial resilience and defense. In this issue of American Journal of Respiratory Cell and Molecular Biology, Wang and colleagues4 describe a previously unrecognized lactylation–m6A axis that couples metabolic reprogramming to RNA regulation of ciliary motility (Figure 1). Using integrated in vitro and in vivo approaches, they show that P aeruginosa directly consumes host-derived lactate and simultaneously suppresses glycolysis, depriving epithelial cells of key metabolic intermediates. This dual metabolic hit leads to reduced histone H3K18 lactylation and subsequent downregulation of the m6A reader YTHDF1. This cascade and loss of m6A modification preferentially destabilizes DNAH5 transcripts, a key dynein motor and critical determinant of ciliary motility. The resulting impairment in mucociliary clearance creates a more favorable environment for bacterial persistence. Their findings highlight a host lactylation–m6A–DNAH5 circuitry that this pathogen exploits to disable epithelial defenses. In the healthy lung, host-derived lactate is used for histone lactylation to maintain m6A marks on mRNA transcripts such as DNAH5, a key protein that maintains ciliary motility and mucociliary clearance. During Pseudomonas aeruginosa infection, the pathogen hijacks host epithelial cell metabolism to directly consume host-derived lactate and suppress glycolysis. This dual metabolic hit results in decreased histone lactylation, decreased m6A reader YTHDF1 expression, and destabilized DNAH5 transcripts, ultimately leading to decreased ciliary motility and mucociliary clearance and creating a more favorable environment for pathogen persistence. Several aspects of this work stand out. First, it expands the scope of lactylation, originally identified as a metabolic-epigenetic signal in macrophages,5,6 into airway epithelial biology. Lactate, long regarded as a metabolic byproduct, emerges as a crucial substrate for maintaining transcriptional and posttranscriptional networks required for ciliary resilience and function. Second, it places m6A methylation, an epitranscriptomic modification with rapidly expanding roles in immunity and development,7 squarely at the center of epithelial host defense and thus highlights a dual-layered mechanism by which microbial perturbations directly suppress mucociliary clearance. By showing that DNAH5 stability depends on YTHDF1-mediated recognition of m6A marks, the authors identify RNA modifications as direct regulators of mucociliary clearance. This 2-pronged strategy highlights the sophistication of pathogen–host interactions. Pseudomonas does not simply block ciliary motion by physical damage or toxin secretion, it reshapes the metabolic and epitranscriptomic landscape of epithelial cells to directly impair pathogen clearance. This work expands our view of airway vulnerability from a structural and ­immunologic defect to include RNA-level regulation. Important questions arise from these discoveries. Could pharmacologic or nutritional modulation of lactate availability restore epithelial defense in chronic P aeruginosa infections? Do similar metabolic–epitranscriptomic interactions occur with other airway pathogens, such as Haemophilus influenzae or Staphylococcus aureus? And, perhaps most provocatively, can we envision therapeutics that restore proper epitranscriptomic homeostasis to bolster mucociliary clearance? While the immediate translational application of m6A-targeting strategies in airway disease may be distant, the conceptual shift is profound. Importantly, RNA modification enzymes are already the subject of drug discovery efforts in oncology,8,9 raising the possibility of repurposing agents already under development to enhance epithelial defense. The novelty of implicating m6A in mucociliary clearance should also not be ignored. m6A is the most prevalent internal modification of eukaryotic mRNA, influencing stability, splicing, and translation. In the immune system, m6A regulates dendritic cell activation, T-cell differentiation, and antiviral responses.7,10 Despite this, studies of m6A in respiratory biology remain sparse. By identifying DNAH5 as a key YTHDF1-dependent transcript, this study firmly establishes epitranscriptomic regulation as a determinant of epithelial barrier function. Moreover, this work raises the intriguing possibility that pathogens broadly exploit epitranscriptomic pathways. Just as bacteria compete for nutrients in the extracellular space, they may compete for or deplete the metabolic cofactors required for RNA modifications. This idea of epitranscriptomic immunity suggests that pathogens do not simply evade immune recognition but rewire fundamental RNA processes to disable host defense. As with any pioneering study, there are important limitations to consider. The reliance on murine in vivo and in vitro systems raises the question of whether the lactylation–m6A axis operates identically in human airways, particularly in the complex microenvironments of cystic fibrosis and COPD. Moreover, the focus on Pseudomonas leaves open whether similar metabolic–epitranscriptomic sabotage occurs with other airway pathogens. The lactylation–m6A–DNAH5 axis presented here4 is compelling but also likely represents only one part of a broader RNA regulatory landscape disrupted during infection. Ultimately, while the translational implications are exciting, practical strategies to modulate lactate metabolism or RNA modification in patients are distant. This study provides a strong reminder that airway defense is not simply mechanical, immunologic, or metabolic but is a combination of all 3, orchestrated through layers of regulation that pathogens have learned to exploit. By uncovering this lactylation–m6A axis, Wang and colleagues offer both a new paradigm and a new target. Furthermore, this study highlights why Pseudomonas remains so difficult to eradicate and why novel host-directed therapies are urgently needed. These insights offer mechanistic clarity and therapeutic hope that by restoring metabolic and epitranscriptomic balance, we might tilt the scale in favor of the host. Supplementary material is available at American Journal of Respiratory Cell and Molecular Biology online. Please see the ICMJE disclosure forms, which have been provided as supplementary material. The authors have no conflicts. Dr Tarling is supported by grants from the National Institutes of Health (HL174008, HL163908, DK138340) and the American Heart Association (23EIA1037961). Dr Redente is supported by grants from the National Institutes of Health (HL147860 and HL149741). No artificial intelligence tools were used in writing this manuscript.