Yi Zhang, Weijia Gu, Fanxuan Zhao, Yingyi Zhang, Feng Zhou, Biya Zeng, Xinyu Wang, Xiang Lin, Xiaoying Jin, Na Liu, Weijie Yang, Songying Zhang, Yongdong Dai
INTRODUCTION: Adenomyosis, which affects > 20% of reproductive-age women, is a major cause of infertility. Defective decidualization of endometrial stromal cells (ESCs) is a key pathogenic feature of adenomyosis; however, the underlying redox-metabolic mechanisms remain unclear. OBJECTIVES: This study aims to define how ferroptosis impairs decidualization and to investigate the cooperative role of solute carrier family 7 member 11 (SLC7A11) and the pentose phosphate pathway (PPP) enzyme glucose-6-phosphate dehydrogenase (G6PD) in maintaining redox homeostasis. METHODS: ratio. RESULTS: Ferroptosis was exacerbated in ESCs from patients with adenomyosis, as evidenced by elevated lipid peroxidation and iron accumulation alongside downregulated SLC7A11 and glutathione peroxidase 4. In both clinical samples and mice with adenomyosis, this ferroptotic phenotype correlated with impaired decidualization. Decidualization upregulated SLC7A11, enhancing the glutathione-based antioxidant system. SLC7A11 expression was positively associated with established markers of endometrial receptivity. Functional studies confirmed that SLC7A11 knockdown and pharmacologic inhibition both disrupted decidualization. Mechanistically, decidualization reprogrammed glucose metabolism, augmenting the PPP and its key enzyme G6PD to generate NADPH. SLC7A11 and G6PD acted synergistically to maintain redox homeostasis by supporting glutathione synthesis. Critically, this axis protected ESCs against iron overload-induced oxidative stress, rescuing decidualization defects. CONCLUSION: The SLC7A11-G6PD axis cooperatively counteracted ferroptosis during decidualization. SLC7A11-G6PD downregulation in adenomyosis resulted in oxidative damage and infertility. Pharmacological targeting of this redox axis may represent a novel therapeutic strategy for restoring endometrial receptivity in adenomyosis.