Abstract
GPX4 is a crucial regulator of ferroptosis, yet its role in mitochondrial dysfunction during myocardial ischemia/reperfusion injury (MI/RI) is unclear. This study aims to clarify the effect and molecular mechanisms of GPX4 in MI/RI. We analyzed the spatiotemporal dynamics of GPX4 during MI/RI and observed high expression levels in border and normal areas but a significant reduction in the ischemic region utilizing spatial transcriptomics, spatial proteomics, and single-cell sequencing. Cardiomyocyte-derived GPX4 notably reduces myocardial damage and mitochondrial dysfunction in MI/RI while also alleviating long-term ventricular remodeling. Mechanistically, our findings reveal that GPX4, through its critical U46 active site, enhances the interaction between BNIP3 and USP20, decreasing ubiquitination at K131 of BNIP3. This process stabilizes BNIP3, promotes mitophagy, improves mitochondrial function, and ultimately preserves cardiac function. Our research defines the role of the GPX4/BNIP3/USP20 complex in MI/RI and uncovers a mechanism linking GPX4 to ferroptosis-related mitochondrial damage, providing valuable insights for advancing ferroptosis studies.
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Data availability
The proteomics data generated in this study have been deposited in the ProteomeXchange Consortium via the PRIDE partner repository under accession code PXD072382. Bulk RNA-seq data generated in this study have been deposited in the Genome Sequence Archive (GSA) under accession codes CRA035515 and CRA035410. Single-cell RNA sequencing data generated in this study have been deposited in the Genome Sequence Archive (GSA) under accession code CRA035546. All datasets are publicly accessible without restriction. Source data are provided with this paper.
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Acknowledgements
We would like to express our sincere gratitude to Mengxin Zhang and Wenting Wang from the scientific research center of Wenzhou Medical University for their invaluable assistance with the immunofluorescence experiment. Additionally, we appreciate Lingli Hou and Yanni Dong from the Scientific Research Center of Wenzhou Medical University for their help in echocardiography. At last, we thank Zhuqi Huang for valuable assistance in uploading the raw mass spectrometry data. This work was supported by the Natural Science Foundation of Zhejiang Province (LQ21H020009 and LMS25H020006 to B.-Z.Y.), Zhejiang Provincial postdoctoral research project (ZJ2024075 to B.-Z.Y.), the Medical and Health Science and Technology Project of Zhejiang Province (2025KY995 to B.-Z.Y.), the National Science Foundation of China (82570321 to B.-Z.Y., 82170242 and 81570454 to D.-L.Y.) and the State Key Laboratory of Transvascular Implantation Devices (012024015 to D.-L.Y.).
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L.-F.Z., Z.-F.C., Y.-C.Z., X.-X.F., Y.-X.Z., F.Y., R.-H.Z., K.-K.Y., D.-R.C., J.-H.L., and X.C. carried out the experiments. B.-Z.Y. contributed to the design of the experiments. B.-Z.Y., and L.-F.Z. participated in the drafting of the article. Z.-Q.H., C.C., D.-L.Y., and W.-J.H. contributed to data collection and analysis. All authors contributed to the article and approved the submitted version.
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Zhong, L., Cheng, Z., Zhang, Y. et al. Cardiomyocyte-derived GPX4 stabilizes BNIP3 to facilitate mitophagy and mitigate myocardial ischemia/reperfusion injury. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71232-2
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DOI: https://doi.org/10.1038/s41467-026-71232-2
