Molecular Signatures of Preeclampsia: The Role of Post‐Translational Protein Modifications

Preeclampsia (PE) is a complex hypertensive disorder of pregnancy characterized by placental dysfunction, systemic inflammation, oxidative stress, and widespread maternal endothelial injury. Although multiple molecular pathways have been implicated in its pathogenesis, the regulatory mechanisms that integrate placental stress with vascular and immune maladaptation remain incompletely understood. Post-translational modifications (PTMs) have emerged as critical regulators of protein function, stability, localization, and signaling, positioning them as key molecular integrators of the pathological processes underlying PE. In this review, we synthesize current evidence linking PTM dysregulation to the major biological processes disrupted in PE, with a particular focus on SUMOylation, ubiquitination, S-nitrosylation, acetylation, and glycosylation. These modifications modulate trophoblast invasion, angiogenic balance, redox homeostasis, immune tolerance, and endothelial signaling across placental, and maternal vascular compartments. We highlight how hypoxia, inflammation, and metabolic stress converge to disrupt PTM-regulating enzyme systems, thereby amplifying placental dysfunction and maternal vascular injury. Emerging evidence supporting PTM crosstalk further underscores the existence of coordinated regulatory networks rather than isolated molecular events. Advances in proteomics, systems biology, and extracellular vesicle profiling have revealed PTM-enriched molecular signatures in maternal circulation that precede clinical disease onset, offering opportunities for early diagnosis and risk stratification. We critically address current limitations in the field, including the predominance of cross-sectional studies, challenges in cell type-specific and temporal resolution, and barriers to clinical implementation. This review positions PTMs as central molecular hubs linking placental stress to systemic vascular dysfunction and highlights their potential to inform future precision medicine approaches in PE.