ENPP1 deficiency drives trophoblast ferroptosis via USP2-SQSTM1 axis, worsening gestational diabetes placental dysfunction

Gestational diabetes mellitus (GDM) is a prevalent pregnancy complication characterized by hyperglycemia, which can lead to significant placental dysfunction and adverse fetal outcomes. Maintaining trophoblast homeostasis is crucial for placental health, but the mechanisms underlying GDM-induced trophoblast injury, particularly the interplay between autophagy and ferroptosis, remain poorly understood. Current treatments primarily focus on glycemic control, often failing to fully mitigate placental damage. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) has been linked to autophagic cell death, suggesting its potential role in these processes and offering a novel therapeutic target for GDM-related placental injury.

Researchers investigated ENPP1's role in autophagy-dependent ferroptosis in the context of GDM using clinical placental tissues from GDM patients, hyperglycemia-treated HTR8/SVneo trophoblast cells, and streptozotocin-induced GDM mice. They performed ubiquitination assays and co-immunoprecipitation to elucidate molecular interactions. Functional studies assessed cellular responses, while therapeutic interventions, such as restoring ENPP1 expression or inhibiting autophagy, were tested in the GDM mouse model to evaluate their impact on placental health and fetal development. The study aimed to clarify how ENPP1 regulates the balance between autophagy and ferroptosis in trophoblasts.

ENPP1 levels were significantly reduced in GDM placentas and this reduction directly correlated with increased ferroptosis and lipid peroxidation. Mechanistically, ENPP1 was found to recruit USP2 (ubiquitin-specific peptidase 2) to inhibit the ubiquitination and subsequent autophagic degradation of SQSTM1 (sequestosome 1), thereby enhancing SQSTM1's stability. This critical interaction maintains cellular balance. > Loss of ENPP1 promoted NCOA4-mediated ferritinophagy, leading to iron overload and ultimately triggering ferroptosis in trophoblast cells. Restoring ENPP1 expression or inhibiting autophagy in GDM mice alleviated placental thinning and reduced fetal growth restriction, demonstrating a direct link between ENPP1 deficiency, ferroptosis, and GDM-related placental pathology. These findings highlight a novel regulatory axis in GDM pathogenesis.