Deferoxamine addresses metabolic dysregulation and urinary tract infections in weight-associated gestational diabetes mellitus

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BACKGROUND: The increasing prevalence of gestational diabetes mellitus (GDM), particularly among overweight or obese individuals, poses significant health risks. Excess iron contributes to oxidative stress, inflammation, and disruptions in immune and metabolic functions in GDM. Deferoxamine (DFO), an iron chelator, may offer a therapeutic solution by restoring immune and metabolic balance. METHODS: We conducted a comprehensive multi-omics analysis using GEO transcriptomic data, applying Weighted Gene Co-expression Network Analysis (WGCNA) and gene set enrichment analysis to identify key immune-metabolic genes. Molecular docking experiments with DFO were performed using AutoDock Vina, and interactions were visualized in PyMOL. Various in vitro assays-CCK-8, qRT-PCR, Western blot, immunofluorescence, ELISA, and colony formation tests-were conducted under high glucose conditions to assess the effects of DFO, focusing on LAMA3 and the PI3K/AKT signaling pathway. RESULTS: Key genes such as CDR2L, LIMCH1, LDLR, and LAMA3 were identified as being improperly regulated in cases of gestational diabetes mellitus (GDM). DFO demonstrated a significant affinity for these targets, especially LDLR. Functionally, DFO was found to improve cell survival during hyperglycemic stress, mitigate oxidative stress, and lower the concentrations of inflammatory cytokines like IL-6, IL-17, and IL-23. Notably, silencing or blocking LAMA3 reversed these effects, inhibiting the PI3K/AKT pathway, increasing apoptosis markers, and decreasing cell proliferation. CONCLUSIONS: DFO holds potential as a targeted treatment for GDM associated with obesity by addressing iron excess and immune-metabolic dysregulation. LAMA3 plays a crucial role in mediating DFO's anti-inflammatory and survival-promoting effects via the PI3K/AKT pathway. Further clinical studies are needed to explore DFO's therapeutic potential in GDM.

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