Abstract
Hepatic ischemia followed by reperfusion (I/R), a major clinical problem during liver surgical procedures, can induce liver injury with severe cell death including ferroptosis which is characterized by iron-dependent accumulation of lipid peroxidation. The HECT domain-containing ubiquitin E3 ligase HUWE1 (also known as MULE) was initially shown to promote apoptosis. However, our preliminary study demonstrates that high expression of HUWE1 in the liver donors corelates with less injury and better hepatic function after liver transplantation in patients. Thus, we investigate the role of HUWE1 in acute liver injury, and identify HUWE1 as a negative ferroptosis modulator through transferrin receptor 1(TfR1). Deficiency of Huwe1 in mice hepatocytes (HKO) exacerbated I/R and CCl4-induced liver injury with more ferroptosis occurrence. Moreover, Suppression of Huwe1 remarkably enhances cellular sensitivity to ferroptosis in primary hepatocytes and mouse embryonic fibroblasts. Mechanistically, HUWE1 specifically targets TfR1 for ubiquitination and proteasomal degradation, thereby regulates iron metabolism. Importantly, chemical and genetic inhibition of TfR1 dramatically diminishes the ferroptotic cell death in Huwe1 KO cells and Huwe1 HKO mice. Therefore, HUWE1 is a potential protective factor to antagonize both aberrant iron accumulation and ferroptosis thereby mitigating acute liver injury. These findings may provide clinical implications for patients with the high-expression Huwe1 alleles.
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Data supporting the present study are available from the corresponding author upon reasonable request.
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Acknowledgements
We appreciate Dr. Tak W Mak (University Health Network, Toronto, Canada) for providing Huwe1-flox mice. We thank Dr. Jixi Li (Fudan University, Shanghai, China), Dr. Xuxu Sun (Shanghai Jiaotong University School of Medicine, Shanghai, China) and Dr. Ming He (Shanghai Jiaotong University School of Medicine, Shanghai, China) for reagents. We thank Academician Prof. Guoqiang Chen (Shanghai Jiaotong University School of Medicine, Shanghai, China) for helpful discussion and suggestions. We also appreciate the support from Shanghai Frontiers Science Center of Cellular Homeostasis and Human diseases, and Core Facility of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine.
Funding
This work was supported by National Natural Science Foundation of China (32070734), Natural Science Foundation of Shanghai (20ZR1430800), the Shanghai Pujiang Program (20PJ1409500) to JZ, National Natural Science Foundation of China (91754205, 91957204, 31771523), Ministry of Science and Technology of China (2019YFA0508602), the Sino-German Mobility Program (M-0140), Program of Shanghai Subject Chief Scientist (19XD1402200) to QZ, Project of Shanghai key clinical specialties (shslczdzk05801) and Innovative Research Team of High-Level Local Universities in Shanghai (SSMU-ZDCX20180802) to QX, Medical-Engineering Cross-Research Fund in “Jiaotong University Star” Program of Shanghai Jiao Tong University (YG2022QN002) to HJ, Project of the Shanghai Municipal Health Commission (20204Y0012) to KH, innovative research team of high-level local universities in Shanghai and Shanghai Science and Technology Commission (20JC1410100).
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YY, QZ and JZ participated in research design and QX provided the clinical samples to support; YW, HJ, and YY performed cell biology experiments; YW, HJ, YY, YW, and HL did the mice experiment analysis; KH collected the patients samples and HJ did the biochemistry and statistical analysis; YJ and JZ performed the ischemia/reperfusion surgery; ZH made the Huwe1-flox mice strain; HJ and XZ did the primary hepatocytes culture; YY, YW and HJ performed data analysis and interpretation; YW and HJ drafted the paper; HJ did the graphical abstract. JZ supervised the study and contributed to the writing of the manuscript. and All authors read and approved the final manuscript.
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All animal experiments were conducted in agreement with the Guide for the Care and Use of Laboratory Animals and approved by the Institutional Animal Care and Use Committee of Shanghai Jiao Tong University School of Medicine (Shanghai, China). This study related to patients has been approved by the Institutional Review Board of Renji Hospital affiliated to Shanghai Jiao Tong University School of Medicine (IRB Reference Number: KY2020-190). The participants or their guardians provided signed consent.
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Wu, Y., Jiao, H., Yue, Y. et al. Ubiquitin ligase E3 HUWE1/MULE targets transferrin receptor for degradation and suppresses ferroptosis in acute liver injury. Cell Death Differ 29, 1705–1718 (2022). https://doi.org/10.1038/s41418-022-00957-6
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DOI: https://doi.org/10.1038/s41418-022-00957-6
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