Antagonism of GPR75 inhibits gestational diabetes mellitus-induced placental tissue injury by preventing activation of the NLRP3 inflammasome

Gestational diabetes mellitus (GDM) is a common pregnancy complication associated with significant maternal and fetal risks. The 20-hydroxyeicosatetraenoic acid (20-HETE) and its receptor GPR75 have been implicated in metabolic dysregulation, but their role in GDM remains unclear. This study investigated the pathophysiological role of the 20-HETE/GPR75 axis in GDM and evaluated the therapeutic potential of a GPR75 antagonist. In a mouse model of GDM, we found significantly elevated levels of 20-HETE in plasma (2.4-fold) and placental tissue (1.6-fold), alongside increased GPR75 expression at both mRNA (2.3-fold, P < 0.01) and protein levels (2.1-fold). Administration of the GPR75 antagonist AAA (10 mg/kg/day) markedly attenuated hyperglycemia (143.3 ± 14.2 vs. 195.2 ± 21.3 mg/dL, P < 0.01), improved Insulin levels (5.7 ± 0.59 vs. 3.9 ± 0.39 mg/dL, P < 0.01), corrected dyslipidemia (TC: 113.5 ± 15.1 vs. 168.7 ± 20.2 mg/dL, P < 0.01; TG: 124.9 ± 13.8 vs. 215.3 ± 23.6 mg/dL, P < 0.01), and improved fetal survival rate (97.2% vs. 81.2%, P < 0.05). Mechanistically, the antagonist reduced oxidative stress (TBARS decreased by 58%, ROS levels reduced by approximately 42%, both P < 0.01), suppressed NLRP3 inflammasome activation (NLRP3 expression reduced by 48%, P < 0.01; IL-1β: 1.7 ± 0.16 vs. 3.5 ± 0.37 ng/g protein, P < 0.01), and inhibited the MAPK p38/NF-κB signaling pathway (p-p38/p38 ratio reduced from 2.8 ± 0.25-1.3 ± 0.13, p-NF-κB p65 from 2.3 ± 0.24-1.2 ± 0.11, both P < 0.01) in the placenta. Our findings demonstrate that the 20-HETE/GPR75 pathway is upregulated in GDM and contributes to its pathophysiology. Targeting GPR75 represents a promising therapeutic strategy for mitigating GDM symptoms and improving placental function.