Ferroptosis-Mediated Placental Dysfunction in the Pathophysiology of Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) is a common metabolic complication of pregnancy associated with adverse maternal and fetal outcomes. Nevertheless, the molecular mechanism of placental dysfunction in GDM are still not clear, especially the role of ferroptosis and its interplay with oxidative stress, inflammation, and angiogenesis.

Placental tissues from GDM pregnancies were examined to assess oxidative stress, antioxidant defense, ferroptosis regulation, inflammatory signaling, and angiogenic pathways. Expression levels of key molecular markers were evaluated, and correlation analyses were performed to identify mechanistic interrelationships.

GDM placenta demonstrated elevated oxidative stress markers, including P22PHOX and TXNIP, accompanied by reduced antioxidant markers, such as HO-1, NQO1, SOD2, and CAT, indicating impaired cellular defense. Ferroptosis regulation was disrupted, as anti-ferroptotic markers GPX4, SLC7A11, and NRF2 were significantly downregulated, while pro-ferroptotic markers TFR1 and ACSL4 were increased, suggesting enhanced iron accumulation and lipid peroxidation. This was accompanied by heightened inflammation, evidenced by increased IL-6, IL-1β, TNF-α, and NF-κB activation, alongside reduced IL-10 expression. Furthermore, angiogenesis was impaired, reflected by decreased VEGFA, HIF-1α, and SDF-1α levels, highlighting poor vascular development in the placenta. Additionally, Correlation analyses demonstrated strong associations between ferroptosis markers and oxidative stress, inflammatory, and angiogenic pathways, suggesting the possible presence of an interconnected regulatory network.

These findings identify ferroptosis as a central regulator of GDM-associated placental dysfunction, through a possible interconnected network of oxidative stress, inflammation, and impaired angiogenesis. Targeting ferroptosis may offer a possible therapeutic option to restore placental function and improve maternal-fetal outcomes in GDM.