Redox report : communications in free radical research · 2026
NOX2/NOX4-associated oxidative stress contributes to G6PD-associated metabolic remodeling and ferroptosis during mice luteolysis.
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Li Fei, Song JiaHao, Zou Wei, Zhang Yulu, Cheng YanMin, Zhao HongRu, Yang Bei, Kuang Haibin
Аннотация
OBJECTIVE: Ferroptosis has been shown to participate in luteolysis, yet the upstream signals and metabolic remodeling that trigger it remain unknown. This study aims to clarify these mechanisms.
METHODS: Physiological postpartum and PGF2α-induced luteolysis models were established in mice. Targeted energy metabolomics, pharmacological inhibition and adenoviral shRNA-mediated knockdown were employed in vivo and in primary luteal cells to measure ferroptosis markers, G6PD activity, NADP⁺/NADPH ratio and NOX2/NOX4 expression.
RESULTS: In both models, luteal regression was accompanied by increased ACSL4, decreased GPx4 and GSH, and elevated Fe2⁺ and lipid peroxidation and NOX2 and NOX4 expression. Metabolic analysis revealed 6-phosphogluconate accumulation, reduced pyruvate and pyruvate kinase M activity, and increased G6PD expression and activity, but NADPH depletion and redox imbalance. In vivo, combined NOX2/NOX4 knockdown reduced ROS accumulation, suppressed G6PD hyperactivation, alleviated ferroptotic injuryand delayed regression Moreover, G6PD inhibition with 6-AN similarly reduced oxidative stress and ferroptosis and partially restored progesterone secretion. In primary luteal cells, G6PD knockdown or 6-AN treatment attenuated PGF2α-induced ferroptosis and improved cell viability. Simultaneously, NOX2/NOX4 silencing, N-acetylcysteine, or Ferrostatin-1 suppressed PGF2α-induced G6PD activation, and attenuated oxidative stress and ferroptosis.
CONCLUSION: NOX2/NOX4-associated oxidative stress contributes to G6PD-associated metabolic remodeling and ferroptosis during mice luteolysis.
METHODS: Physiological postpartum and PGF2α-induced luteolysis models were established in mice. Targeted energy metabolomics, pharmacological inhibition and adenoviral shRNA-mediated knockdown were employed in vivo and in primary luteal cells to measure ferroptosis markers, G6PD activity, NADP⁺/NADPH ratio and NOX2/NOX4 expression.
RESULTS: In both models, luteal regression was accompanied by increased ACSL4, decreased GPx4 and GSH, and elevated Fe2⁺ and lipid peroxidation and NOX2 and NOX4 expression. Metabolic analysis revealed 6-phosphogluconate accumulation, reduced pyruvate and pyruvate kinase M activity, and increased G6PD expression and activity, but NADPH depletion and redox imbalance. In vivo, combined NOX2/NOX4 knockdown reduced ROS accumulation, suppressed G6PD hyperactivation, alleviated ferroptotic injuryand delayed regression Moreover, G6PD inhibition with 6-AN similarly reduced oxidative stress and ferroptosis and partially restored progesterone secretion. In primary luteal cells, G6PD knockdown or 6-AN treatment attenuated PGF2α-induced ferroptosis and improved cell viability. Simultaneously, NOX2/NOX4 silencing, N-acetylcysteine, or Ferrostatin-1 suppressed PGF2α-induced G6PD activation, and attenuated oxidative stress and ferroptosis.
CONCLUSION: NOX2/NOX4-associated oxidative stress contributes to G6PD-associated metabolic remodeling and ferroptosis during mice luteolysis.