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Background <p>Neonatal hypoxic-ischemic encephalopathy (HIE) triggers systemic oxidative stress and redox imbalance, contributing to multi-organ injury. Urine is a noninvasive matrix for longitudinal profiling of molecular responses, yet time-resolved proteomic studies in HIE are limited.</p> Methods <p>We performed longitudinal SWATH-MS proteomic profiling of urine from term neonates with moderate-to-severe HIE treated with therapeutic hypothermia (<i>n</i> = 16) and non-asphyxiated controls (<i>n</i> = 19) at six time points during the first eight days of life. Proteins identified in ≥ 80% of samples were quantified, and differential abundance, temporal clustering, pathway enrichment, and upstream regulatory networks were analyzed.</p> Results <p>Approximately 1,000 proteins were quantified per sample. A total of 438 proteins were differentially abundant, with most changes transient and ten persistent. Early HIE urine showed marked elevation of hemoglobin subunits and sequential induction of haptoglobin and hemopexin, indicating staged heme scavenging and oxidative stress responses. Pathway enrichment revealed inhibition of neutrophil-associated innate immunity and activation of heme detoxification, lipoprotein remodeling, and PPAR signaling. Temporal clustering demonstrated stage-specific proteomic transitions, with partial normalization toward controls by days 6-8. Ingenuity Pathway Analysis identified six upstream regulators: Interleukin-1 alpha (IL1A), Tumor Necrosis Factor (TNF), ETS Homologous Factor (EHF), Peroxisome Proliferator-Activated Receptor Delta (PPARD), Thioredoxin-Interacting Protein (TXNIP), and Solute Carrier Family 2 Member 3 (SLC2A3), coordinating inflammation, redox control, and metabolic adaptation.</p> Conclusions <p>We identified transient and sustained proteomic shifts that trace coordinated changes in oxidative stress, heme metabolism, and metabolic adaptation, alongside key regulators such as IL1A, TNF, EHF, PPARD, and TXNIP. The progression from early injury-related divergence to partial recovery by day 8 highlights the dynamic nature of post-insult remodeling. These findings support urinary proteomics as a robust, non-invasive tool for probing HIE pathophysiology and point to promising biomarker and pathway candidates for future studies.</p>

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Time-resolved urinary proteomics reveals heme-associated oxidative stress responses in neonatal hypoxic-ischaemic encephalopathy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月4日

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  • Magdalena Zasada,
  • Maciej Suski,
  • Marta Olszewska,
  • Aleksandra Kowalik,
  • Natalia Łapińska,
  • Weronika Pogoda,
  • Przemko Kwinta

摘要

Background

Neonatal hypoxic-ischemic encephalopathy (HIE) triggers systemic oxidative stress and redox imbalance, contributing to multi-organ injury. Urine is a noninvasive matrix for longitudinal profiling of molecular responses, yet time-resolved proteomic studies in HIE are limited.

Methods

We performed longitudinal SWATH-MS proteomic profiling of urine from term neonates with moderate-to-severe HIE treated with therapeutic hypothermia (n = 16) and non-asphyxiated controls (n = 19) at six time points during the first eight days of life. Proteins identified in ≥ 80% of samples were quantified, and differential abundance, temporal clustering, pathway enrichment, and upstream regulatory networks were analyzed.

Results

Approximately 1,000 proteins were quantified per sample. A total of 438 proteins were differentially abundant, with most changes transient and ten persistent. Early HIE urine showed marked elevation of hemoglobin subunits and sequential induction of haptoglobin and hemopexin, indicating staged heme scavenging and oxidative stress responses. Pathway enrichment revealed inhibition of neutrophil-associated innate immunity and activation of heme detoxification, lipoprotein remodeling, and PPAR signaling. Temporal clustering demonstrated stage-specific proteomic transitions, with partial normalization toward controls by days 6-8. Ingenuity Pathway Analysis identified six upstream regulators: Interleukin-1 alpha (IL1A), Tumor Necrosis Factor (TNF), ETS Homologous Factor (EHF), Peroxisome Proliferator-Activated Receptor Delta (PPARD), Thioredoxin-Interacting Protein (TXNIP), and Solute Carrier Family 2 Member 3 (SLC2A3), coordinating inflammation, redox control, and metabolic adaptation.

Conclusions

We identified transient and sustained proteomic shifts that trace coordinated changes in oxidative stress, heme metabolism, and metabolic adaptation, alongside key regulators such as IL1A, TNF, EHF, PPARD, and TXNIP. The progression from early injury-related divergence to partial recovery by day 8 highlights the dynamic nature of post-insult remodeling. These findings support urinary proteomics as a robust, non-invasive tool for probing HIE pathophysiology and point to promising biomarker and pathway candidates for future studies.