Metabolic Reprogramming in Preeclampsia across Early- and Late-onset Phenotypes: An Integrated Mitochondrial, Glycolytic, and Lipid Transport Framework – A Systematic Review

Metabolic dysfunction has long been recognized as a feature of preeclampsia, yet it is usually treated as a downstream consequence rather than a defining biological process. In recent years, advances in metabolomics, transcriptomics, lipidomics, and placental biology have challenged this view, suggesting that altered energy handling may sit closer to the core of disease heterogeneity. We therefore conducted a systematic review to examine whether metabolic reprogramming provides a unifying framework linking early-onset and late-onset preeclampsia (LOPE) across placental and maternal compartments. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidance, comprehensive searches of major databases and registers identified 1285 records. After duplicate removal, screening, and full-text assessment, 36 studies met predefined inclusion criteria encompassing human clinical studies, multi-omics analyses, mechanistic placental investigations, and relevant animal models. Risk of bias was assessed using the Risk of Bias 2 tool, Newcastle–Ottawa Scale, Systematic Review Center for Laboratory Animal Experimentation, and AMSTAR-2, as appropriate. Data were synthesized qualitatively with emphasis on pathway-level convergence rather than single-marker effects. Across study types, a consistent pattern emerged in which placental hypoxia and impaired spiral artery remodeling were associated with mitochondrial dysfunction, reduced oxidative phosphorylation, compensatory glycolytic activation, and altered pyruvate handling, particularly in early-onset disease. LOPE, while sharing some placental signals, more frequently aligned with systemic metabolic susceptibility, lipid remodeling, and chronic low-grade inflammation. Lipid transport abnormalities, angiogenic–metabolic coupling, and emerging pathways such as ferroptosis and microbiome–host interactions further refined these phenotypes. Taken together, the evidence supports energy-pathway switching as a central organizing principle in preeclampsia rather than a secondary epiphenomenon. Framing early- and late-onset disease through integrated metabolic programs offers a biologically coherent basis for subtype stratification, biomarker development, and precision therapeutic strategies.