Lactate and Lactylation in Pulmonary Hypertension: Comprehensive Landscape and Future Perspectives

Figures

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  Figure 1. History of the discovery and development of lactate and lactylation. Representative milestone events leading to the discovery and development of lactate and lactylation are enumerated in the figure. Key milestones include: (1) 1780: Carl Wilhelm Scheele first discovered lactate in sour milk. (2) 1843: Johann Scherer detected lactate in human blood during shock, initially fueling its reputation as a harmful byproduct of hypoxia. (3) 1921: Otto Warburg described the "Warburg Effect," noting that tumor cells preferentially produce lactate even in the presence of oxygen. (4) 1986: George Brooks proposed the "Lactate Shuttle Theory," identifying lactate as a key energy substrate and signaling molecule between tissues. (5) 2019: A breakthrough study by Zhang et al. identified histone lysine lactylation (Kla) as a novel epigenetic modification, directly linking cellular metabolism to gene transcription. (6) 2020: Gaffney et al. discovered that lactylation also occurs on non-histone metabolic enzymes, exerting negative feedback on glycolytic flux.

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  Figure 2. Metabolism of lactate and lactylation. This schematic provides a comprehensive overview of lactate homeostasis and its conversion into lactylation modifications. Intracellular lactate is primarily produced from glucose via glycolysis (catalyzed by LDH) or secondary sources like glutaminolysis, and it can be converted back to pyruvate or cleared via the PDH complex to enter the TCA cycle for oxidative phosphorylation. The transmembrane flux of lactate is regulated by specific transporters: MCT1 directs lactate transport according to the transmembrane lactate gradient, while MCT4 is responsible for lactate efflux. These metabolic dynamics are coupled with the regulation of protein lactylation, where p300/EP300, ACSS2, and AARS1/2 function as lactoyltransferases that catalyze the transfer of lactyl groups to lysine residues on target proteins, whereas HDACs and sirtuins act as delactylases that catalyze the removal of these modifications. Abbreviations used in the figure: AARSs: Aminoacyl-tRNA synthetases; MCT1/4: Monocarboxylate transporter 1/4; LDHA/B: Lactate dehydrogenase A/B; PDH: Pyruvate dehydrogenase; GLUD: Glutamate dehydrogenase;ɑ-KG: ɑ-ketoglutarate; OAA: Oxaloacetate;…

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  Figure 3. Potential molecular mechanisms of lactate/lactylation in PH. This conceptual model illustrates how the lactate-lactylation axis acts as a central metabolic hub driving PH pathogenesis through five distinct pathological pillars. In PASMC Proliferation, lactate stimulates proliferation in a concentration-dependent manner by elevating D1 and PCNA levels. H3K18la, H4K15la and protein Kla directly fuel this hyper-proliferative phenotype. Additionally, histone lactylation upregulates Prelamin A to induce PASMC senescence, which subsequently triggers a SASP and the release of IL-6 to stimulate neighboring cell proliferation via paracrine signaling. For the immune-inflammatory response, lactate facilitates TLR4-NF-κB signaling and activates Th17 cells. Concurrently, H3K18la triggers the release of pro-inflammatory cytokines (including IL-6, IL-1β, and TNF-α) from PASMCs and promotes the activation of M2 macrophages. In pulmonary fibrosis, lactate promotes myofibroblast differentiation through the ERK/DRP1-ROS and TGF-β1 pathways. Macrophage H3K18la further drives the expression of pro-fibrotic factors (ARG1, PDGF-A, TSP-1, VEGFA) and mediates progression via the YTHDF1/N6-methyladenosine…