Cuproptosis: a novel mechanism linking placental metabolic stress to trophoblast injury in preeclampsia.

Preeclampsia (PE) is characterized by placental hypoxia, metabolic stress, trophoblast dysfunction, and impaired spiral artery remodeling, but the mechanisms linking these abnormalities remain incompletely understood. Cuproptosis, a recently identified form of regulated cell death driven by copper-dependent aggregation of lipoylated tricarboxylic acid cycle proteins, may provide a mechanistic link between placental metabolic stress and trophoblast injury. Here, we propose a hypothesis in which hypoxia-induced glycolytic reprogramming and lactate accumulation promote histone H3K18 lactylation, activate GRHL2, and increase SLC31A1/CTR1-mediated copper uptake. Subsequent FDX1-dependent copper reduction, DLAT aggregation, Fe-S cluster loss, and mitochondrial proteotoxic stress may preferentially affect mitochondria-rich villous syncytiotrophoblasts, while also impairing EVT function. Cuproptosis may interact with ferroptosis and oxidative stress through shared metal-redox and mitochondrial vulnerabilities. Although current evidence does not establish cuproptosis as an initiating cause of PE, it may amplify placental dysfunction. Targeting copper transport, mitochondrial stress, or pathway-specific biomarkers warrants further investigation.