The DOI matches its Crossref record; 40 of the 40 references it cites were found in a registry or an index.
Legumain promotes tubular ferroptosis by facilitating chaperone-mediated autophagy of GPX4 in AKI
Open accessAbstract
Legumain is required for maintenance of normal kidney homeostasis. However, its role in acute kidney injury (AKI) is still unclear. Here, we induced AKI by bilateral ischemia-reperfusion injury (IRI) of renal arteries or folic acid in lgmnWT and lgmnKO mice. We assessed serum creatinine, blood urea nitrogen, histological indexes of tubular injury, and expression of KIM-1 and NGAL. Inflammatory infiltration was evaluated by immunohistological staining of CD3 and F4/80, and expression of TNF-α, CCL-2, IL-33, and IL-1α. Ferroptosis was evaluated by Acsl4, Cox-2, reactive oxygen species (ROS) indexes H 2 DCFDA and DHE, MDA and glutathione peroxidase 4 (GPX4). We induced ferroptosis by hypoxia or erastin in primary mouse renal tubular epithelial cells (mRTECs). Cellular survival, Acsl4, Cox-2, LDH release, ROS, and MDA levels were measured. We analyzed the degradation of GPX4 through inhibition of proteasomes or autophagy. Lysosomal GPX4 was assessed to determine GPX4 degradation pathway. Immunoprecipitation (IP) was used to determine the interactions between legumain, GPX4, HSC70, and HSP90. For tentative treatment, RR-11a was administrated intraperitoneally to a mouse model of IRI-induced AKI. Our results showed that legumain deficiency attenuated acute tubular injury, inflammation, and ferroptosis in either IRI or folic acid-induced AKI model. Ferroptosis induced by hypoxia or erastin was dampened in lgmnKO mRTECs compared with lgmnWT control. Deficiency of legumain prevented chaperone-mediated autophagy of GPX4. Results of IP suggested interactions between legumain, HSC70, HSP90, and GPX4. Administration of RR-11a ameliorated ferroptosis and renal injury in the AKI model. Together, our data indicate that legumain promotes chaperone-mediated autophagy of GPX4 therefore facilitates tubular ferroptosis in AKI.
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Cites
Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death
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Regulation of Ferroptotic Cancer Cell Death by GPX4
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Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease
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ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition
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Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice
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Self-citationFSP1 is a glutathione-independent ferroptosis suppressor
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Ferroptosis: Death by Lipid Peroxidation
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Cited by
GPX4 in cell death, autophagy, and disease
Xie, Y., Kang, R., Klionsky, D. J., & Tang, D. (2023) · Autophagy · doi:10.1080/15548627.2023.2218764 · Cited by 623
GPX4: The hub of lipid oxidation, ferroptosis, disease and treatment
Liu, Y., Wan, Y., Jiang, Y., Zhang, L., & Cheng, W. (2023) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2023.188890 · Cited by 528
GPX4, ferroptosis, and diseases
Zhang, W., Liu, Y., Liao, Y., Zhu, C., & Zou, Z. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.116512 · Cited by 426
Chaperone‐mediated autophagy: Molecular mechanisms, biological functions, and diseases
Yao, R., & Shen, J. (2023) · MedComm · doi:10.1002/mco2.347 · Cited by 111
Tripathy, R. K., Frohock, Z., Wang, H., Cary, G. A., Keegan, S., Carter, G. W., & Li, Y. (2025) · npj Systems Biology and Applications · doi:10.1038/s41540-025-00519-9 · Cited by 36
Metadata
- Authors
- Chen, C., Wang, D., Yu, Y., Zhao, T., Min, N., Wu, Y., Kang, L., Zhao, Y., Du, L., Zhang, M., Gong, J., Zhang, Z., Zhang, Y., Mi, X., Yue, S., & Tan, X.
- Venue
- Cell Death & Disease
- Published
- 2021-01-11
- Volume
- 12
- Issue
- 1
- Pages
- 65-65
- ISSN
- 2041-4889 (ISSN-L)
- OpenAlex
- W3119155918
- Cited by
- 293
- References
- 40
- FWCI
- 30.07
- Type
- journal article
- Language
- en
- Open access
- gold
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- Chen, C., Wang, D., Yu, Y., Zhao, T., Min, N., Wu, Y., Kang, L., Zhao, Y., Du, L., Zhang, M., Gong, J., Zhang, Z., Zhang, Y., Mi, X., Yue, S., & Tan, X. (2021). Legumain promotes tubular ferroptosis by facilitating chaperone-mediated autophagy of GPX4 in AKI. Cell Death & Disease. https://doi.org/10.1038/s41419-020-03362-4
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