Oxidative stress-dependent placental cell death and crosstalk as therapeutic targets: focus on preeclampsia

Preeclampsia (PE) is a severe pregnancy-specific disorder that endangers maternal and fetal health worldwide, particularly in low- and middle-income countries. This heterogeneous syndrome stems from abnormal placentation and manifests after 20 weeks of gestation. Its predominant clinical feature is new-onset hypertension, frequently accompanied by proteinuria or target organ dysfunction, such as liver or kidney dysfunction. PE pathogenesis is multifactorial, involving abnormal placental development, immune dysregulation, vascular dysfunction, and other contributing factors. Among these, oxidative stress plays a critical role, as placental ischemia and hypoxia lead to excessive generation of reactive oxygen species (ROS), overwhelming the body's antioxidant defenses and thereby triggering cell death. Notably, cell death plays an indispensable role in embryonic development and the maintenance of organismal homeostasis. Accordingly, this review summarizes evidence on redox-related cell death pathways in PE, including apoptosis, autophagy, necroptosis, pyroptosis, and ferroptosis, as well as the oxidative stress-associated signaling pathways involved in these processes. Based on published data, we suggest that molecular interplay among different redox-related modes of placental trophoblast cell death may occur in PE. Furthermore, the risk of PE is associated with the concentration of copper, an essential prenatal trace element, in the body. This observation has prompted the hypothesis that cuproptosis, a recently discovered form of copper-dependent cell death, may represent a potential mechanism underlying PE pathogenesis. Targeting cuproptosis or implementing combined interventions targeting multiple cell death pathways could provide novel therapeutic strategies for PE.