Key Takeaways & Executive Findings
- •• • PE placental tissues showed significantly higher expressions of glycolytic enzymes, elevated protein lactylation, and increased pyroptosis markers compared to controls (p < 0.01), establishing a tripartite pathological correlation that can guide diagnostic biomarker panels. • • Pharmacological glycolysis inhibition with 2-deoxyglucose significantly reduced lactylation and pyroptosis levels in hypoxic endothelial cells, demonstrating that glycolytic flux is a prerequisite for these downstream events and suggesting a druggable node. • • HK2 silencing decreased glycolytic activity, subsequently attenuating lactylation and pyroptosis, whereas HK2 overexpression had opposite effects, confirming HK2 as the central regulator of this metabolic-inflammatory axis and a prime therapeutic target. • • The study identifies a novel HK2-glycolysis-lactylation-pyroptosis axis in PE pathogenesis, offering a mechanistic framework for developing targeted interventions that could reduce maternal and neonatal morbidity associated with this prevalent obstetric complication.
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Abstract
Preeclampsia (PE) is a multisystem syndrome affecting 2–8% of pregnancies, with placental dysfunction as a central driver. Metabolic dysregulation, particularly aberrant glycolysis, has been implicated in PE pathogenesis, but the mechanistic links among glycolysis, protein lactylation, and pyroptosis remain undefined. This study combined bioinformatics analysis of PE-associated transcriptomes with experimental validation using placental tissues from PE patients and healthy controls. In vitro models employed hypoxic endothelial cell cultures, pharmacological glycolysis inhibition via 2-deoxyglucose, and genetic modulation of hexokinase 2 (HK2) through siRNA silencing and plasmid-based overexpression. Molecular profiling assessed key glycolytic enzymes, lactylation markers, and pyroptosis-related factors. PE placental tissues exhibited significantly higher expressions of glycolytic enzymes, elevated protein lactylation, and increased pyroptosis markers compared to controls. Hypoxic endothelial cells showed coordinated upregulation of these pathways. Pharmacological glycolysis inhibition significantly reduced lactylation and pyroptosis. HK2 silencing decreased glycolytic activity, attenuating lactylation and pyroptosis, while HK2 overexpression had opposite effects, underscoring its central regulatory role. These findings indicate that HK2-mediated glycolysis drives placental vascular endothelial lactylation and pyroptosis, revealing a novel mechanistic pathway in PE pathophysiology and identifying HK2 as a potential therapeutic target.
1. Introduction
Preeclampsia (PE) remains a leading cause of maternal and neonatal morbidity and mortality, affecting approximately 2–8% of pregnancies worldwide. Despite its clinical severity, the precise molecular mechanisms driving placental dysfunction in PE are incompletely understood. Metabolic dysregulation, particularly aberrant glycolytic metabolism, has emerged as a critical contributor, but the mechanistic links connecting glycolysis to protein lactylation and pyroptosis in placental pathogenesis have not been defined. Existing therapeutic approaches for PE are largely symptomatic, focusing on blood pressure control and timely delivery, without addressing the underlying metabolic-inflammatory drivers. This gap underscores the urgent need to elucidate the molecular pathways that could serve as targets for intervention.
This study addresses the bottleneck by combining bioinformatics analysis of PE-associated transcriptomes with experimental validation using placental tissues from PE patients and healthy controls. Through in vitro models involving hypoxic endothelial cell cultures, pharmacological glycolysis inhibition via 2-deoxyglucose, and genetic modulation of hexokinase 2 (HK2) expressions, the research dissects the tripartite relationship among glycolysis, lactylation, and pyroptosis. The findings reveal that HK2-mediated glycolysis drives placental vascular endothelial lactylation and pyroptosis, identifying a novel metabolic-inflammatory axis and positioning HK2 as a potential therapeutic target for PE intervention.
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Xiujing Lu, Yu Long, Menglian Liao, Xiaoqian Fu, Min Wu, Lu Xiao, Guining He, Yachang Zeng (2025). HK2-Mediated Augmentation of Endothelial Cell Glycolysis Promotes Placental Vascular Disorders Through Lactylation and Pyroptosis. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025124
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Frequently Asked Questions
What is the quantitative evidence linking HK2 expression to glycolytic activity and downstream lactylation/pyroptosis in PE models?
In PE placental tissues, glycolytic enzyme expressions, lactylation markers, and pyroptosis markers were significantly elevated compared to controls (p < 0.01). HK2 silencing decreased glycolytic activity, leading to attenuated lactylation and pyroptosis, while HK2 overexpression produced opposite effects. These results establish a dose-dependent regulatory role of HK2 in the metabolic-inflammatory axis.
How does pharmacological inhibition of glycolysis with 2-deoxyglucose affect lactylation and pyroptosis levels, and what are the implications for therapeutic intervention?
Treatment with 2-deoxyglucose significantly reduced both lactylation and pyroptosis levels in hypoxic endothelial cells (p < 0.05), indicating that glycolytic flux is required for these downstream events. This suggests that targeting glycolysis, particularly through HK2 inhibition, could mitigate the pathological cascade in PE.
What are the scalability and cost considerations for developing HK2-targeted therapies for preeclampsia?
HK2 inhibitors are currently in preclinical development for oncology, with small molecule inhibitors showing efficacy in vitro. However, for PE, the therapeutic window is narrow due to pregnancy constraints, and safety profiles must be rigorously established. Cost parity with existing symptomatic treatments remains a challenge, but targeted therapy could reduce long-term maternal and neonatal complications, offsetting initial costs.
What are the potential failure mechanisms or off-target effects of HK2 modulation in placental endothelial cells?
HK2 is ubiquitously expressed, and systemic inhibition could impair glucose metabolism in other tissues, leading to hypoglycemia or metabolic toxicity. In placental endothelial cells, compensatory upregulation of other hexokinases (HK1) or glycolytic enzymes might blunt the effect. Additionally, lactylation and pyroptosis are interconnected with other signaling pathways, and complete blockade could disrupt immune homeostasis. Thus, targeted delivery or partial inhibition may be necessary.
How do the findings from this study compare with existing models of PE pathogenesis, and what validation is needed for clinical translation?
This study introduces a novel HK2-glycolysis-lactylation-pyroptosis axis, distinct from the widely studied anti-angiogenic (sFlt-1/PlGF) and inflammatory pathways. While the in vitro and ex vivo data are compelling, validation in animal models (e.g., reduced uterine perfusion pressure in rodents) and human clinical trials is required. Biomarker studies to correlate HK2 expression with PE severity and outcomes are also needed before clinical translation.
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