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

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

doi:10.1016/j.jare.2026.02.030

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

J Adv Res. 2026 Feb 19:S2090-1232(26)00162-1. doi: 10.1016/j.jare.2026.02.030. Online ahead of print.

Authors

Yi Zhang¹, Weijia Gu¹, Fanxuan Zhao¹, Yingyi Zhang¹, Feng Zhou¹, Biya Zeng¹, Xinyu Wang¹, Xiang Lin¹, Xiaoying Jin¹, Na Liu¹, Weijie Yang¹, Songying Zhang², Yongdong Dai³

Affiliations

¹ Department of Obstetrics and Gynecology, Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility, Zhejiang Provincial Clinical Research Center for Reproductive Health and Disease, Assisted Reproduction Unit, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China.
² Department of Obstetrics and Gynecology, Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility, Zhejiang Provincial Clinical Research Center for Reproductive Health and Disease, Assisted Reproduction Unit, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China. Electronic address: zhangsongying@zju.edu.cn.
³ Department of Obstetrics and Gynecology, Zhejiang Key Laboratory of Precise Protection and Promotion of Fertility, Zhejiang Provincial Clinical Research Center for Reproductive Health and Disease, Assisted Reproduction Unit, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China. Electronic address: daiyongdong@zju.edu.cn.

PMID: 41722688
DOI: 10.1016/j.jare.2026.02.030

Abstract

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.

Keywords: Adenomyosis; Decidualization; Ferroptosis; G6PD; NADPH–glutathione axis; SLC7A11.