Diabetes & Metabolism Journal

Original Articles

Basic and Translational Research
Rbbp6-Mediated Bmal1 Ubiquitination Inhibits YAP1 Signaling Pathway to Promote Ferroptosis in Diabetes-Induced Testicular Damage: Yuan Tian, Zhiqiang Zhu, Jun Qiao, Bei Liu, Yuehai Xiao; Diabetes Metab J. 2025;49(2):210-224. Published online November 6, 2024; DOI: https://doi.org/10.4093/dmj.2024.0099

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Background
Diabetes-induced testicular damage (DITD) is a common complication of diabetes. We investigated underlying mechanism of retinoblastoma-binding protein 6 (Rbbp6)-mediated brain and muscle ARNT-like 1 (Bmal1) ubiquitination in modulating ferroptosis in DITD.
Methods
Spermatogenic cell apoptosis and viability were measured by flow cytometry and cell counting kit 8 (CCK-8), respectively. The impact of Rbbp6 and Bmal1 on ferroptosis was assessed by determining expression of ferroptosis markers glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), and levels of malondialdehyde (MDA), glutathione (GSH), iron, and lipid peroxidation. Co-immunoprecipitation was performed to determine the interaction between Rbbp6 and Bmal1, as well as the ubiquitination level of Bmal1. The expression levels of Rbbp6, Bmal1, Yes-associated protein 1 (YAP1), ferroptosis markers, and testicular steroidogenic enzymes were tested by Western blot.
Results
Bmal1 protein expression was significantly downregulated, while Rbbp6 was upregulated in DITD mouse model and high glucose (HG)-induced GC-1 spg cells. Overexpression of Bmal1 improved testicular injury in diabetic mice, reduced 4-hydroxynonenal (4-HNE), MDA, iron levels, and increased expression levels of GPX4, SLC7A11, GSH, as well as testicular steroidogenic enzymes. Rbbp6 decreased Bmal1 level through promoting its ubiquitination. Meanwhile, Rbbp6 knockdown inhibited the ferroptosis of HG-induced GC-1 spg cells, which were abolished by silencing Bmal1. In addition, knockdown of YAP1 or treatment with ferroptosis inducer erastin blocked the above effects caused by Bmal1 overexpression.
Conclusion
Rbbp6-mediated Bmal1 ubiquitination suppressed YAP1 pathway, promoting ferroptosis in DITD. This study highlighted Rbbp6/Bmal1/YAP1 axis as a potential therapeutic target for mitigating DITD.

Citations

Citations to this article as recorded by

Melatonin‐engineered MSCs‐exosomes deliver USP4 to stabilise ARNTL and inhibit clock rhythmic ferroptosis for enhanced flap survival
Xiaoqiong Jiang, Yu Wang, Xuanlong Zhang, Huiming Deng, Liangyu Fang, Chaire Tafadzwa, Jiangnan Yao, Hao Chen, Anqi Ye, Kailiang Zhou, Xiangwei Ling, Jian Xiao
Clinical and Translational Medicine.2026;[Epub] CrossRef
GALNT3-mediated AKT1 glycosylation activates the AKT1/CREB signaling pathway to inhibit high glucose-induced spermatogenic cell apoptosis and mitochondrial dysfunction
Yong Zhao, Jia Luo, Lu Wu
Biochemical and Biophysical Research Communications.2026; 802: 153329. CrossRef
Guilu Erxian glue mitigates spermatogenesis dysfunction through HIF-1α/SLC7A11-mediated ferroptosis inhibition: An integrated metabolomics and network pharmacology study
Chuying Tang, Wen Sheng, Xianrui Li, Wei Fu, Meixin Lin, Zheng Wen, Wei Luo, Zezheng Zhang, Qingxia Zheng, Xing Zhou, Jin Ding
Phytomedicine.2025; 148: 157321. CrossRef

Basic Research
N⁶-Methyladenosine Methyltransferase METTL3 Alleviates Diabetes-Induced Testicular Damage through Modulating TUG1/Clusterin Axis: Yuan Tian, Yue-Hai Xiao, Chao Sun, Bei Liu, Fa Sun; Diabetes Metab J. 2023;47(2):287-300. Published online January 19, 2023; DOI: https://doi.org/10.4093/dmj.2021.0306

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Background
The present study investigated the regulatory effects of N6-methyladenosine (m6A) methyltransferase like-3 (METTL3) in diabetes-induced testicular damage.
Methods
In vivo diabetic mice and high glucose (HG) treated GC-1 spg cells were established. The mRNA and protein expressions were determined by real-time quantitative polymerase chain reaction, Western blot, immunofluorescence and immunohistochemistry staining. Levels of testosterone, blood glucose, cell viability, and apoptosis were detected by enzyme-linked immunosorbent assay, MTT, and flow cytometry, respectively. Molecular interactions were verified by RNA immunoprecipitation and RNA pull-down assay. Histopathological staining was performed to evaluate testicular injury.
Results
METTL3 and long non-coding RNA taurine up-regulated 1 (lncRNA TUG1) were downregulated in testicular tissues of diabetic mice and HG-treated GC-1 spg cells. METTL3 overexpression could reduce the blood glucose level, oxidative stress and testicular damage but enhance testosterone secretion in diabetic mouse model and HG-stimulated GC-1 spg cells. Mechanically, METTL3-mediated m6A methylation enhanced the stability of TUG1, then stabilizing the clusterin mRNA via recruiting serine and arginine rich splicing factor 1. Moreover, inhibition of TUG1/clusterin signaling markedly reversed the protective impacts of METTL3 overexpression on HG-stimulated GC-1 spg cells.
Conclusion
This study demonstrated that METTL3 ameliorated diabetes-induced testicular damage by upregulating the TUG1/clusterin signaling. These data further elucidate the potential regulatory mechanisms of m6A modification on diabetes-induced testicular injury.

Citations

Citations to this article as recorded by

GALNT3-mediated AKT1 glycosylation activates the AKT1/CREB signaling pathway to inhibit high glucose-induced spermatogenic cell apoptosis and mitochondrial dysfunction
Yong Zhao, Jia Luo, Lu Wu
Biochemical and Biophysical Research Communications.2026; 802: 153329. CrossRef
Rbbp6-Mediated Bmal1 Ubiquitination Inhibits YAP1 Signaling Pathway to Promote Ferroptosis in Diabetes-Induced Testicular Damage
Yuan Tian, Zhiqiang Zhu, Jun Qiao, Bei Liu, Yuehai Xiao
Diabetes & Metabolism Journal.2025; 49(2): 210. CrossRef
METTL3 promotes podocyte pyroptosis in diabetic nephropathy through N 6 -methyladenosine modification of TRIM29 mRNA
Xiaohong Xu, Xiaolin Huang, Ce Zhang, Xia Mi, Chi Zhang, Fei Hua, Liexiang Zhang
Renal Failure.2025;[Epub] CrossRef
The m6A transferase METTL3 regulates high glucose-induced proliferation and apoptosis of human lens epithelial cells through the lncRNA TUG1/KHSRP/p38MAPK signaling axis
Yuxuan Li, Ziyi Yao, Xiaoqin Gao, Yaxin Niu, Ziqing Gao, Shengqun Jiang
Experimental Eye Research.2025; 258: 110492. CrossRef
METTL3 alleviates renal tubular mitochondrial dysfunction by regulating the TUG1/PGC-1a axis in an IGF2BP2-dependent manner in diabetic nephropathy
Tong Chen, Juan Wang, Yanyan Xu, Yonghong Zhu, Ying Jin, Qiuling Fan
Renal Failure.2025;[Epub] CrossRef
m6A modification of non‑coding RNA: Mechanisms, functions and potential values in human diseases (Review)
Qian Yi, Yi Liao, Wei Sun, Jiachen Li, Dahang Yang, Hongxi Shang, Weichao Sun
International Journal of Molecular Medicine.2025; 56(4): 1. CrossRef
The role of m6A methyltransferase METTL3 in metabolism-related diseases: Mechanism and clinical implications
Libao Cui, Wang Jun, Yan Ying, Hengrong Fang
Pharmacological Research.2025; 221: 107962. CrossRef
Regulation of m6A methylation in the immune microenvironment in the development of diabetes mellitus
Haoyue Deng, Qiang Liu, Yanning Gong, Yue Qiu
Journal of Translational Medicine.2025;[Epub] CrossRef
Mechanism of the traditional Chinese medicine SMBJ alleviates diabetes mellitus-induced Leydig cell dysfunction in rats testes
Wenxiu Zhang, Yuanyuan Liu, Li Tong, Yihan Jin, Chao Gao, Yugui Cui, Baofang Jin, Dalin Sun
Scientific Reports.2025;[Epub] CrossRef
Negative Regulation of LINC01013 by METTL3 and YTHDF2 Enhances the Osteogenic Differentiation of Senescent Pre‐Osteoblast Cells Induced by Hydrogen Peroxide
Jiaxin Song, Yuejun Wang, Zhao Zhu, Wanqing Wang, Haoqing Yang, Zhaochen Shan
Advanced Biology.2024;[Epub] CrossRef
Diabetes and diabetic associative diseases: An overview of epigenetic regulations of TUG1
Mohammed Ageeli Hakami
Saudi Journal of Biological Sciences.2024; 31(5): 103976. CrossRef
BRD7 facilitates ferroptosis via modulating clusterin promoter hypermethylation and suppressing AMPK signaling in diabetes-induced testicular damage
Yuehai Xiao, Zongjian Liang, Jun Qiao, Zhiqiang Zhu, Bei Liu, Yuan Tian
Molecular Medicine.2024;[Epub] CrossRef
Roles of m6A modification in regulating PPER pathway in cadmium-induced pancreatic β cell death
Yifei Sun, Rongxian Li, Wenhong Li, Nan Zhang, Guofen Liu, Bo Zhao, Zongqin Mei, Shiyan Gu, Zuoshun He
Ecotoxicology and Environmental Safety.2024; 282: 116672. CrossRef
METTL14-Mediated m6A Modification of TUG1 Represses Ferroptosis in Alzheimer's Disease via Inhibiting GDF15 Ubiquitination
Xunhu Gu, Yuanqing Song, Xu Liu, Zhijuan Cheng, Jun Min, Yangbo Zhang
Frontiers in Bioscience-Landmark.2024;[Epub] CrossRef

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