Iron-lipid crosstalk in the progression from gestational diabetes to preeclampsia: proteomic discovery and targeted validation.

OBJECTIVES: The pathogenesis underlying the transition from gestational diabetes mellitus to pre-eclampsia (GDM-PE) has not been fully elucidated. Here, we performed plasma proteomic profiling to analyze the interplay between iron and lipid pathways throughout disease progression.

METHODS: We conducted a two-stage study design. In the discovery phase, proteomic profiling was performed in 5 GDM-PE patients and 10 GDM controls to identify critical hub proteins and dysregulated pathways. We then performed targeted validation in an independent first-trimester cohort consisting of 20 normal pregnant women, 14 GDM patients, and 6 GDM-PE patients. Levels of six key proteins: adiponectin, P-selectin, soluble transferrin receptor (sTFR), ferritin, fetuin-A, and apolipoprotein B, were measured using ELISA, and protein networks and clinical correlations were further analyzed.

RESULTS: Proteomic analysis identified 218 differentially expressed proteins in patients with GDM-PE, which were significantly enriched in the ferroptosis pathway; adiponectin and P-selectin were identified as key hub proteins. Targeted validation confirmed significant trends of increasing sTFR and decreasing fetuin-A across the disease continuum (P for trend < 0.05), suggesting a potential alteration in iron-lipid metabolic balance that may be related to ferroptosis-associated pathways. We observed progressive network rewiring: the physiological adiponectin-sTFR correlation was abolished in GDM, while a pathological fetuin-A-apolipoprotein B negative association emerged and intensified with disease severity, although not reaching statistical significance in the smaller subgroups. These molecular changes were mirrored in clinical associations: adiponectin correlated inversely with fasting glucose in GDM, whereas in GDM-PE, apolipoprotein B correlated strongly with 1-hour oral glucose tolerance test and the adiponectin-hemoglobin relationship reversed dramatically (r = -0.93, P = 0.008). Furthermore, logistic regression identified fetuin-A as an independent protective factor (adjusted odds ratio = 0.83, 95% CI: 0.65-0.96, P = 0.048) for GDM and sTFR as a risk factor (OR = 1.03, 95% CI: 1.01-1.06, P = 0.03) for disease severity.

CONCLUSIONS: Our integrated analysis proposes a three-stage pathogenic model for GDM-PE, characterized by progressive lipid-iron axis dysregulation, which may be associated with ferroptosis-related processes but requires further validation. This network-based framework positions the core proteins of this axis as promising targets for early risk stratification.