Synergistic regulation of SLC7A11 and glucose-6-phosphate dehydrogenase in redox homeostasis governs decidualization: a mechanistic insight into adenomyosis-related infertility

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 Eutopic endometrial tissues were obtained from 24 patients with adenomyosis and 22 fertile controls. A tamoxifen-induced mouse adenomyosis model (n = 20) and the pseudopregnancy decidualization assay were also used. Primary human ESCs were decidualized in vitro . Experimental approaches comprised RNA interference knockdown, adenoviral overexpression, stable-isotope tracing, liquid chromatography–mass spectrometry metabolomics, and iron modulation. Decidualization was assessed by evaluating insulin-like growth factor-binding protein 1 and prolactin expression, reactive oxygen species, lipid peroxidation, and nicotinamide adenine dinucleotide phosphate (NADPH)/NADP + 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.