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ABSTRACT Chronic kidney disease (CKD) is a major global health concern and the third leading cause of premature death. Renal fibrosis is the primary process driving the progression of CKD,

but the mechanisms behind it are not fully understood, making treatment options limited. Here, we find that the E3 ligase TRIM65 is a positive regulator of renal fibrosis. Deletion of TRIM65

results in a reduction of pathological lesions and renal fibrosis in mouse models of kidney fibrosis induced by unilateral ureteral obstruction (UUO)- and folic acid. Through screening with

a yeast-hybrid system, we identify a new interactor of TRIM65, the mammalian cleavage factor I subunit CFIm25 (NUDT21), which plays a crucial role in fibrosis through alternative

polyadenylation (APA). TRIM65 interacts with NUDT21 to induce K48-linked polyubiquitination of lysine 56 and proteasomal degradation, leading to the inhibition of TGF-β1-mediated SMAD and

ERK1/2 signaling pathways. The degradation of NUDT21 subsequently altered the length and sequence content of the 3′UTR (3′UTR-APA) of several pro-fibrotic genes including _Col1a1_, _Fn-1_,

_Tgfbr1_, _Wnt5a_, and _Fzd2_. Furthermore, reducing NUDT21 expression via hydrodynamic renal pelvis injection of adeno-associated virus 9 (AAV9) exacerbated UUO-induced renal fibrosis in

the normal mouse kidneys and blocked the protective effect of TRIM65 deletion. These findings suggest that TRIM65 promotes renal fibrosis by regulating NUDT21-mediated APA and highlight

TRIM65 as a potential target for reducing renal fibrosis in CKD patients. Access through your institution Buy or subscribe This is a preview of subscription content, access via your

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* Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS THE E3 UBIQUITIN LIGASE TRIM39 MODULATES RENAL FIBROSIS INDUCED BY

UNILATERAL URETERAL OBSTRUCTION THROUGH REGULATING PROTEASOMAL DEGRADATION OF PRDX3 Article Open access 09 January 2024 NEDDYLATION OF RHOA IMPAIRS ITS PROTEIN DEGRADATION AND PROMOTES

RENAL INTERSTITIAL FIBROSIS PROGRESSION IN DIABETIC NEPHROPATHY Article Open access 03 February 2025 _PKD1_ AND _PKD2_ MRNA CIS-INHIBITION DRIVES POLYCYSTIC KIDNEY DISEASE PROGRESSION

Article Open access 15 August 2022 DATA AVAILABILITY The data analyzed during this study are included in this published article. Additional supporting data are available from the

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signaling: From tissue fibrosis to therapeutic opportunities. Chem Biol Interact. 2023;369:110289. CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS We appreciate Dr. Hongbin

Shu and Dr. Shu Li (School of Medicine, Wuhan University) for providing HA-Ub mutant plasmids. We thank Alan Jiang (The First Affiliated Hospital, Jiangxi Medical College, Nanchang

University) for microscopy assistance. FUNDING This work was supported by grants from the National Natural Science Foundation of China (82160133, 31960147, and 32170793), Jiangxi Provincial

Natural Science Foundation (20212ACB216005, 20224ACB216013, 20224BAB206007, and 20212BAB206086). AUTHOR INFORMATION Author notes * These authors contributed equally: Sisi Wei, Xuan Huang.

AUTHORS AND AFFILIATIONS * Department of Anesthesiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China Sisi Wei, Tao Chen, Juan Tian, 

Tingyu Pan, Lv Zhang, Xian Kuang, Enjun Lei & Yong Li * The National Engineering Research Center for Bioengineering Drugs and the Technologies; Institute of Translational Medicine,

Jiangxi Medical College, Nanchang University, Nanchang, 330031, China Xuan Huang, Qing Zhu, Tao Xie & Qi Zhang * Department of Biological Sciences, College of Sciences and Arts, Michigan

Technological University, Houghton, MI, 49931-1295, USA Yan Zhang Authors * Sisi Wei View author publications You can also search for this author inPubMed Google Scholar * Xuan Huang View

author publications You can also search for this author inPubMed Google Scholar * Qing Zhu View author publications You can also search for this author inPubMed Google Scholar * Tao Chen

View author publications You can also search for this author inPubMed Google Scholar * Yan Zhang View author publications You can also search for this author inPubMed Google Scholar * Juan

Tian View author publications You can also search for this author inPubMed Google Scholar * Tingyu Pan View author publications You can also search for this author inPubMed Google Scholar *

Lv Zhang View author publications You can also search for this author inPubMed Google Scholar * Tao Xie View author publications You can also search for this author inPubMed Google Scholar *

Qi Zhang View author publications You can also search for this author inPubMed Google Scholar * Xian Kuang View author publications You can also search for this author inPubMed Google

Scholar * Enjun Lei View author publications You can also search for this author inPubMed Google Scholar * Yong Li View author publications You can also search for this author inPubMed 

Google Scholar CONTRIBUTIONS YL conceived and designed the study, prepared the figures, analyzed data, and participated in the paper writing. SW and XH performed the experiments, analyzed

the data, and wrote the first draft of the manuscript. QZhu, TC, JT, TP, and XK conducted experiments during the study. LZ, TX, and QZ bred and genotyped the mice. YZ critically revised the

manuscript for important intellectual content. EL reviewed the manuscript. All authors approved and contributed to the manuscript. CORRESPONDING AUTHOR Correspondence to Yong Li. ETHICS

DECLARATIONS COMPETING INTERESTS The authors declare no competing interests. ETHICS APPROVAL All animal procedures were approved by The Institutional Animal Care and Use Committee of The

First Affiliated Hospital of Nanchang University and performed in accordance with the ARRIVE guideline. All methods were carried out in accordance with relevant guidelines and regulations.

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Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Wei, S., Huang, X., Zhu, Q. _et al._ TRIM65 deficiency alleviates renal fibrosis through NUDT21-mediated alternative

polyadenylation. _Cell Death Differ_ 31, 1422–1438 (2024). https://doi.org/10.1038/s41418-024-01336-z Download citation * Received: 08 April 2024 * Revised: 19 June 2024 * Accepted: 25 June

2024 * Published: 29 June 2024 * Issue Date: November 2024 * DOI: https://doi.org/10.1038/s41418-024-01336-z SHARE THIS ARTICLE Anyone you share the following link with will be able to read

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