G6PD-mediated pentose phosphate pathway modulates ferroptosis in chronic intermittent hypoxia-induced vascular endothelial injury
- 1Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
- 2Department of Respiratory and Critical Care Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- 3Respiratory Disease Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
Abstract
PurposeChronic intermittent hypoxia (CIH), a defining pathophysiological feature of obstructive sleep apnea (OSA), imposes recurrent hypoxia–reoxygenation stress on the vascular endothelium. The metabolic–redox mechanisms connecting CIH to endothelial ferroptosis remain incompletely defined. This study investigated the pentose phosphate pathway (PPP)/glucose-6-phosphate dehydrogenase (G6PD)/NADPH axis in CIH-induced endothelial ferroptosis and evaluated the protective effects of Liproxstatin-1 (Lip-1).MethodsRats and rat aortic endothelial cells (RAOECs) were exposed to CIH and treated with Lip-1 or vehicle. Endothelial injury, ferroptosis-associated changes, and PPP-related metabolism were assessed using histopathology, Western blotting, flow cytometry, biochemical assays, electron microscopy, and targeted metabolomics. G6PD knockdown was used to examine its contribution to Lip-1-mediated protection.ResultsIn rats, CIH caused aortic endothelial injury accompanied by reduced GPX4 and SLC7A11 expression and increased ACSL4 expression. In RAOECs, CIH induced ferroptosis-associated changes, including increased Fe²+, lipid peroxidation, and mitochondrial abnormalities. CIH was also associated with reduced PPP-related metabolites, G6PD protein expression, and the NADPH/NADP+ ratio. Lip-1 attenuated endothelial injury and ferroptotic responses while restoring PPP/G6PD/NADPH-associated metabolic and redox parameters. G6PD knockdown partially attenuated the protective response to Lip-1.ConclusionCIH-associated endothelial ferroptotic injury is closely linked to altered PPP/G6PD-dependent redox metabolism. Lip-1 protects the endothelium while restoring this metabolic–redox axis, with G6PD contributing to its antioxidant and anti-ferroptotic effects.
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BibTeX
@article{chen2026g6pdmediated,
title = {{G6PD-mediated pentose phosphate pathway modulates ferroptosis in chronic intermittent hypoxia-induced vascular endothelial injury}},
author = {Wenqian Chen and Wenqian Chen and Wenqian Chen and Jia Chen and Jia Chen and Jia Chen and Hansheng Xie and Hansheng Xie and Hansheng Xie and Fan Wei and Fan Wei and Fan Wei and Shiyuan Huang and Shiyuan Huang and Shiyuan Huang and Xiaoyu Deng and Xiaoyu Deng and Xiaoyu Deng and Yaqi Liu and Yaqi Liu and Yaqi Liu and Qichang Lin and Qichang Lin and Qichang Lin and Ningfang Lian and Ningfang Lian and Ningfang Lian},
journal = {Frontiers in Physiology},
year = {2026},
month = nov,
doi = {10.3389/fphys.2026.1971105},
url = {https://doi.org/10.3389/fphys.2026.1971105},
note = {CC BY},
}
RIS
TY - JOUR
TI - G6PD-mediated pentose phosphate pathway modulates ferroptosis in chronic intermittent hypoxia-induced vascular endothelial injury
AU - Wenqian Chen
AU - Wenqian Chen
AU - Wenqian Chen
AU - Jia Chen
AU - Jia Chen
AU - Jia Chen
AU - Hansheng Xie
AU - Hansheng Xie
AU - Hansheng Xie
AU - Fan Wei
AU - Fan Wei
AU - Fan Wei
AU - Shiyuan Huang
AU - Shiyuan Huang
AU - Shiyuan Huang
AU - Xiaoyu Deng
AU - Xiaoyu Deng
AU - Xiaoyu Deng
AU - Yaqi Liu
AU - Yaqi Liu
AU - Yaqi Liu
AU - Qichang Lin
AU - Qichang Lin
AU - Qichang Lin
AU - Ningfang Lian
AU - Ningfang Lian
AU - Ningfang Lian
PY - 2026
DA - 2026/11/09
JO - Frontiers in Physiology
DO - 10.3389/fphys.2026.1971105
UR - https://doi.org/10.3389/fphys.2026.1971105
AB - PurposeChronic intermittent hypoxia (CIH), a defining pathophysiological feature of obstructive sleep apnea (OSA), imposes recurrent hypoxia–reoxygenation stress on the vascular endothelium. The metabolic–redox mechanisms connecting CIH to endothelial ferroptosis remain incompletely defined. This study investigated the pentose phosphate pathway (PPP)/glucose-6-phosphate dehydrogenase (G6PD)/NADPH axis in CIH-induced endothelial ferroptosis and evaluated the protective effects of Liproxstatin-1 (Lip-1).MethodsRats and rat aortic endothelial cells (RAOECs) were exposed to CIH and treated with Lip-1 or vehicle. Endothelial injury, ferroptosis-associated changes, and PPP-related metabolism were assessed using histopathology, Western blotting, flow cytometry, biochemical assays, electron microscopy, and targeted metabolomics. G6PD knockdown was used to examine its contribution to Lip-1-mediated protection.ResultsIn rats, CIH caused aortic endothelial injury accompanied by reduced GPX4 and SLC7A11 expression and increased ACSL4 expression. In RAOECs, CIH induced ferroptosis-associated changes, including increased Fe²+, lipid peroxidation, and mitochondrial abnormalities. CIH was also associated with reduced PPP-related metabolites, G6PD protein expression, and the NADPH/NADP+ ratio. Lip-1 attenuated endothelial injury and ferroptotic responses while restoring PPP/G6PD/NADPH-associated metabolic and redox parameters. G6PD knockdown partially attenuated the protective response to Lip-1.ConclusionCIH-associated endothelial ferroptotic injury is closely linked to altered PPP/G6PD-dependent redox metabolism. Lip-1 protects the endothelium while restoring this metabolic–redox axis, with G6PD contributing to its antioxidant and anti-ferroptotic effects.
SN - 1664-042X
ER -