Kaempferol ameliorates gestational diabetes mellitus by regulating STAT3-associated AIM2 inflammasome activation and ferroptotic injury in trophoblasts

Abstract

Introduction To investigate the protective effects of kaempferol (KPF) against gestational diabetes mellitus (GDM) and elucidate its underlying molecular mechanisms. Methods A GDM rat model was established to assess metabolic abnormalities, inflammation, oxidative stress, and placental injury following KPF treatment. In vitro, high glucose (HG)-stimulated HTR-8/SVneo trophoblast cells were used to investigate the protective mechanisms of KPF. Mitochondrial dysfunction, lipid peroxidation, ferroptosis-related alterations, and AIM2 inflammasome activation were evaluated. STAT3 knockdown and AIM2 overexpression were further performed to determine their roles in HG-induced trophoblast injury. Results KPF significantly improved glucose and lipid metabolism, reduced inflammatory cytokine levels, alleviated placental injury, and decreased oxidative stress in GDM rats. In HG-stimulated trophoblasts, KPF attenuated mitochondrial dysfunction, lipid peroxidation, and ferroptosis-related alterations by restoring GPX4 and SLC7A11 expression and inhibiting AIM2 inflammasome activation. Mechanistically, KPF suppressed STAT3 activation, while STAT3 knockdown reduced STAT1/IRF1 activation and AIM2 expression under hyperglycemic conditions. AIM2 overexpression aggravated ferroptosis-related changes and inflammatory responses. Conclusion KPF alleviates GDM-associated placental dysfunction by modulating STAT3-associated signaling and AIM2 inflammasome activation, thereby reducing ferroptosis-related injury and inflammatory activation in trophoblasts. These findings provide new insights into the mechanisms of GDM and support KPF as a potential therapeutic candidate.