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

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.