Objective:

To explore the role of cuproptosis in linking placental metabolic stress to trophoblast injury in preeclampsia.

Approach:

• Hypothesis Development: Proposes that hypoxia-driven glycolytic reprogramming and lactate accumulation lead to histone H3K18 lactylation, activating GRHL2 and enhancing copper uptake, resulting in trophoblast damage.
• Evidence Review: Reviews clinical studies linking copper dyshomeostasis to preeclampsia and identifies differentially expressed cuproptosis-associated genes in placental tissues.
• Pathway Proposal: Suggests a pathway where placental hypoxia induces lactate accumulation, which in turn modifies histones and affects copper metabolism, leading to trophoblast cuproptosis.

Key Findings:

• In a case-control study involving 88 women in the third trimester, significantly higher serum copper concentrations were reported in patients with preeclampsia, alongside lower thiol levels.
• Findings from a systematic review and meta-analysis of 34 studies indicated that the relationship between maternal serum copper and preeclampsia varied significantly by geographic region.
• Lower concentrations of copper, zinc, selenium, and other metals have been observed in placental tissue from preeclampsia pregnancies.

Interpretation:

Existing evidence does not demonstrate that cuproptosis initiates preeclampsia, although it may intensify placental dysfunction.

Limitations:

• Total serum copper may not accurately reflect the labile copper pool available to trophoblasts due to most circulating copper being bound to ceruloplasmin.
• Systemic copper measurements could be confounded by inflammation and variations in nutritional status.

Conclusion:

Further investigation into copper transport, mitochondrial stress, and pathway-specific biomarkers is warranted to clarify the role of cuproptosis in preeclampsia.