CCN5 Drives Leydig Cell Aging and Testicular Dysfunction: Insights into Fibrosis, Lipid Dysregulation, and Therapeutic Potential
Leydig cells’ (LCs’) senescence is an important reason for the decline of testicular function in elderly men. Cellular communication network factor 5 (CCN5) regulates lipid metabolism and cellular fibrosis through multiple mechanisms. However, its role in LCs’ aging and the underlying molecular mech...
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American Association for the Advancement of Science (AAAS)
2025-01-01
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| Series: | Research |
| Online Access: | https://spj.science.org/doi/10.34133/research.0762 |
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| author | Xiaoli Tan Yanghua Xu Ningjing Ou Yuzhuo Chen Wanyi Xia Emily Xing Ren Mo Hao Bo Zhitao Han Jiarong Xu Zepeng Dong Yingbo Dai Yuxin Tang Liangyu Zhao |
| author_facet | Xiaoli Tan Yanghua Xu Ningjing Ou Yuzhuo Chen Wanyi Xia Emily Xing Ren Mo Hao Bo Zhitao Han Jiarong Xu Zepeng Dong Yingbo Dai Yuxin Tang Liangyu Zhao |
| author_sort | Xiaoli Tan |
| collection | DOAJ |
| description | Leydig cells’ (LCs’) senescence is an important reason for the decline of testicular function in elderly men. Cellular communication network factor 5 (CCN5) regulates lipid metabolism and cellular fibrosis through multiple mechanisms. However, its role in LCs’ aging and the underlying molecular mechanisms remain unclear. This study aimed to elucidate the effects and molecular mechanisms by which CCN5 drives aging phenotypes in LCs and to evaluate the potential of targeting CCN5 as a therapeutic strategy for testicular aging. CCN5 expression was located in LCs and elevated in aged testis. Overexpression of CCN5 led to LCs’ aging and testis dysfunction. Extracellularly, CCN5 activated β-catenin and SMAD2/3 phosphorylation, promoting the expression of fibrosis-related genes. Intracellularly, CCN5 did not affect de novo cholesterol synthesis-related genes but changed the balance of cholesterol transporters. CCN5 bound to and reduced ring finger protein 213 (RNF213) protein levels. RNF213 knockdown activated forkhead box O, p16, and p21, resulting in SA-β-gal activation, reduced cell proliferation, and lipid droplet loss. In aged mice, CCN5 knockdown improved testicular atrophy, restored lipid droplet content and testosterone synthesis, and enhanced physical endurance and sexual behavior. In summary, CCN5 drives LCs’ aging and testicular dysfunction maybe via promoting fibrosis and lipid droplet loss. Targeting CCN5 offers a promising strategy to treat testicular aging and associated reproductive endocrine disorders. |
| format | Article |
| id | doaj-art-9a2efb7025df4ee18f341a67a760166a |
| institution | DOAJ |
| issn | 2639-5274 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | Article |
| series | Research |
| spelling | doaj-art-9a2efb7025df4ee18f341a67a760166a2025-08-20T02:47:43ZengAmerican Association for the Advancement of Science (AAAS)Research2639-52742025-01-01810.34133/research.0762CCN5 Drives Leydig Cell Aging and Testicular Dysfunction: Insights into Fibrosis, Lipid Dysregulation, and Therapeutic PotentialXiaoli Tan0Yanghua Xu1Ningjing Ou2Yuzhuo Chen3Wanyi Xia4Emily Xing5Ren Mo6Hao Bo7Zhitao Han8Jiarong Xu9Zepeng Dong10Yingbo Dai11Yuxin Tang12Liangyu Zhao13Department of Urology, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China.Department of Urology, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China.Department of Urology, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China.Department of Urology, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China.Department of Traditional Chinese Medicine, The Fifth Affiliated Hospital, University of Sun Yat-sen, Zhuhai, China.Cedars-Sinai Medical Center, Los Angeles, CA, USA.Department of Urology, Inner Mongolia People’s Hospital, Inner Mongolia Urological Institute, Hohhot, Inner Mongolia 010017, China.NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, Hunan, China.Department of Urology, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China.Department of Urology, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China.Department of Urology, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China.Department of Urology, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China.Department of Urology, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China.Department of Urology, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, Guangdong, China.Leydig cells’ (LCs’) senescence is an important reason for the decline of testicular function in elderly men. Cellular communication network factor 5 (CCN5) regulates lipid metabolism and cellular fibrosis through multiple mechanisms. However, its role in LCs’ aging and the underlying molecular mechanisms remain unclear. This study aimed to elucidate the effects and molecular mechanisms by which CCN5 drives aging phenotypes in LCs and to evaluate the potential of targeting CCN5 as a therapeutic strategy for testicular aging. CCN5 expression was located in LCs and elevated in aged testis. Overexpression of CCN5 led to LCs’ aging and testis dysfunction. Extracellularly, CCN5 activated β-catenin and SMAD2/3 phosphorylation, promoting the expression of fibrosis-related genes. Intracellularly, CCN5 did not affect de novo cholesterol synthesis-related genes but changed the balance of cholesterol transporters. CCN5 bound to and reduced ring finger protein 213 (RNF213) protein levels. RNF213 knockdown activated forkhead box O, p16, and p21, resulting in SA-β-gal activation, reduced cell proliferation, and lipid droplet loss. In aged mice, CCN5 knockdown improved testicular atrophy, restored lipid droplet content and testosterone synthesis, and enhanced physical endurance and sexual behavior. In summary, CCN5 drives LCs’ aging and testicular dysfunction maybe via promoting fibrosis and lipid droplet loss. Targeting CCN5 offers a promising strategy to treat testicular aging and associated reproductive endocrine disorders.https://spj.science.org/doi/10.34133/research.0762 |
| spellingShingle | Xiaoli Tan Yanghua Xu Ningjing Ou Yuzhuo Chen Wanyi Xia Emily Xing Ren Mo Hao Bo Zhitao Han Jiarong Xu Zepeng Dong Yingbo Dai Yuxin Tang Liangyu Zhao CCN5 Drives Leydig Cell Aging and Testicular Dysfunction: Insights into Fibrosis, Lipid Dysregulation, and Therapeutic Potential Research |
| title | CCN5 Drives Leydig Cell Aging and Testicular Dysfunction: Insights into Fibrosis, Lipid Dysregulation, and Therapeutic Potential |
| title_full | CCN5 Drives Leydig Cell Aging and Testicular Dysfunction: Insights into Fibrosis, Lipid Dysregulation, and Therapeutic Potential |
| title_fullStr | CCN5 Drives Leydig Cell Aging and Testicular Dysfunction: Insights into Fibrosis, Lipid Dysregulation, and Therapeutic Potential |
| title_full_unstemmed | CCN5 Drives Leydig Cell Aging and Testicular Dysfunction: Insights into Fibrosis, Lipid Dysregulation, and Therapeutic Potential |
| title_short | CCN5 Drives Leydig Cell Aging and Testicular Dysfunction: Insights into Fibrosis, Lipid Dysregulation, and Therapeutic Potential |
| title_sort | ccn5 drives leydig cell aging and testicular dysfunction insights into fibrosis lipid dysregulation and therapeutic potential |
| url | https://spj.science.org/doi/10.34133/research.0762 |
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