Elevated expression of glycolytic genes as a prominent feature of early-onset preeclampsia: insights from integrative transcriptomic analysis

Introduction: Preeclampsia (PE), a notable pregnancy-related disorder, leads to 40,000+ maternal deaths yearly. Recent research shows PE divides into early-onset (EOPE) and late-onset (LOPE) subtypes, each with distinct clinical features and outcomes. However, the molecular characteristics of various subtypes are currently subject to debate and are not consistent. Methods: We integrated transcriptomic expression data from a total of 372 placental samples across 8 publicly available databases via combat algorithm. Then, a variety of strategies including Random Forest Recursive Feature Elimination (RF-RFE), differential analysis, oposSOM, and Weighted Correlation Network Analysis were employed to identify the characteristic genes of the EOPE and LOPE subtypes. Finally, we conducted in vitro experiments on the key gene HK2 in HTR8/SVneo cells to explore its function. Results: Our results revealed a complex classification of PE placental samples, wherein EOPE manifests as a highly homogeneous sample group characterized by hypoxia and HIF1A activation. Among the core features is the upregulation of glycolysis-related genes, particularly HK2, in the placenta-an observation corroborated by independent validation data and single-cell data. Building on the pronounced correlation between HK2 and EOPE, we conducted in vitro experiments to assess the potential functional impact of HK2 on trophoblast cells. Additionally, the LOPE samples exhibit strong heterogeneity and lack distinct features, suggesting a complex molecular makeup for this subtype. Unsupervised clustering analysis indicates that LOPE likely comprises at least two distinct subtypes, linked to cell-environment interaction and cytokine and protein modification functionalities. Discussion: In summary, these findings elucidate potential mechanistic differences between the two PE subtypes, lend support to the hypothesis of classifying PE based on gestational weeks, and emphasize the potential significant role of glycolysis-related genes, especially HK2 in EOPE.