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Deltex E3 ubiquitin ligase 2 prevents sepsis-induced myocardial injury through degrading TfR1 via promoting K27-linked ubiquitination

Cell Death & Differentiation (2026)Cite this article

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Abstract

Sepsis, a life-threatening systemic inflammatory condition, frequently leads to myocardial injury-a complication for which current therapeutic strategies demonstrate limited efficacy. Here, we explored the potential role and therapeutic implications of Deltex E3 ubiquitin ligase 2 (DTX2) in sepsis-induced myocardial injury. Our results demonstrated that DTX2 expression was significantly upregulated in septic patients, mice models, and lipopolysaccharide (LPS)-stimulated cardiomyocytes. Notably, Dtx2 deficiency markedly aggravated sepsis-induced myocardial hypertrophy, fibrosis, ferroptosis, and mitochondrial dysfunction. In contrast, cardiac-specific overexpression of Dtx2 improved cardiac function in vivo, highlighting its protective role in septic cardiomyopathy. Mechanistically, DTX2 was found to directly interact with transferrin receptor 1 (TfR1) through its DTC domain, mediating K27-linked ubiquitination at lysine 39, which facilitated TfR1 degradation and regulated iron metabolism. Importantly, pharmacological inhibition of ferroptosis counteracted the detrimental effects of Dtx2 deficiency in both LPS-challenged cells and mice. Moreover, genetic silencing of TfR1 considerably suppressed ferroptosis and ameliorated myocardial injury in Dtx2 knockout septic mice. The findings indicate that DTX2 exerts protective effects against abnormal iron accumulation and ferroptosis, thereby alleviating myocardial injury induced by sepsis. These insights could have therapeutic implications for patients with reduced DTX2 expression.

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Fig. 1: DTX2 is upregulated in sepsis-induced myocardial injury.
Fig. 2: Dtx2 deletion impairs cardiac function and aggravates myocardial hypertrophy and fibrosis during sepsis.
Fig. 3: Cardiac-specific overexpression of Dtx2 improves cardiac function and alleviates sepsis-induced myocardial hypertrophy and fibrosis.
Fig. 4: DTX2 interacts TfR1 and promotes its degradation by removing K27-linked ubiquitination.
Fig. 5: DTX2 suppresses ferroptosis through regulating iron metabolism in vivo.
Fig. 6: DTX2 reverses mitochondrial dysfunction and ROS production.
Fig. 7: TfR1 knockdown improves cardiac dysfunction, hypertrophy and fibrosis in Dtx2 knockout septic mice.
Fig. 8: TfR1-mediates ferroptosis is essential for the regulation of DTX2 on sepsis-induced myocardial injury.

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Data availability

All data generated or analysed during this study are included in this published article and its supplementary information files.

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Acknowledgements

We would like to thank Xi Wang (Tiantan Hospital of Capital Medical University, Beijing, China) for providing ubiquitin and its mutants plasmids.

Funding

This work was supported by the National Natural Science Foundation of China (No. 82272221, 82202403, 82172170, 82372195); the Tianjin Natural Science Foundation (No. 24JCQNJC00600, 24JCYBJC01010); the National College Students’ Innovative Entrepreneurial Training Plan Program (No. 202510062034).

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Author notes

  1. These authors contributed equally: Chang Liu, Jia Liu.

Authors and Affiliations

  1. Division of Medical Technology, Tianjin Medical University, Tianjin, China

    Chang Liu, Jia Liu, Mingchen Yin, Runze Li, Caihong Fan, Yixing Chen & Yanna Shen

  2. Department of Gastroenterology, Shengli Oilfield Central Hospital, Dongying, China

    Lihong Guo & Zhi Qi

  3. Department of Molecular Pharmacology, School of Medicine, Nankai University; Department of Cardiology, Beichen Hospital, Nankai University, Tianjin, China

    Zhi Qi

  4. Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin, China

    Zhi Qi

  5. The First Department of Critical Care Medicine, The First Affiliated Hospital of Shihezi University, Shihezi, China

    Zhi Qi

  6. Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin, China

    Zhi Qi

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Contributions

CL conceived and performed the study idea, analyzed the data, and wrote the manuscript. JL performed the experiments and analyzed the data. MY, RL, CF, YC, and LG performed the research. ZQ and YS conceived and supervised the project, and revised the manuscript.

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Correspondence to Zhi Qi or Yanna Shen.

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All methods were performed in accordance with the relevant guidelines and regulations. All animal experiments were approved by the Experimental Animal Ethics Committee of Tianjin Medical University. No human subjects involved in this study.

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Liu, C., Liu, J., Yin, M. et al. Deltex E3 ubiquitin ligase 2 prevents sepsis-induced myocardial injury through degrading TfR1 via promoting K27-linked ubiquitination. Cell Death Differ (2026). https://doi.org/10.1038/s41418-026-01690-0

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