The downregulation of PEPCK mediated cuproptosis is involved in triclosan induced reproductive damage in mouse testes via triggering ROS overproduction

  • Free Radic Biol Med. 2026 Sep:253:770-784. doi: 10.1016/j.freeradbiomed.2026.06.015.
Yanjun Ding  1 ,  Yifan Hong  2 ,  Xiazhu Zhou  3 ,  Jing Chen  4 ,  Haohui Tang  5 ,  Binrong Sun  6 ,  Fengming Ji  7 ,  Jinwen Mi  8 ,  Chunlan Long  9 ,  Lianju Shen  10 ,  Shengde Wu  11 ,  Yuexin Wei  12 ,  Guanghui Wei  13
Affiliations
  • 1. Department of Urology Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders. 400014, Chongqing, China; Chongqing Key Laboratory of Structural Birth Defect and Reconstruction. 400014, Chongqing, China; Children Urogenital Development and Tissue Engineering of Chongqing Education Commission of China, Chongqing, 400014, China. Electronic address: [email protected].
  • 2. Department of Urology Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders. 400014, Chongqing, China; Chongqing Key Laboratory of Structural Birth Defect and Reconstruction. 400014, Chongqing, China; Children Urogenital Development and Tissue Engineering of Chongqing Education Commission of China, Chongqing, 400014, China. Electronic address: [email protected].
  • 3. Department of Urology Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders. 400014, Chongqing, China; Chongqing Key Laboratory of Structural Birth Defect and Reconstruction. 400014, Chongqing, China; Children Urogenital Development and Tissue Engineering of Chongqing Education Commission of China, Chongqing, 400014, China. Electronic address: [email protected].
  • 4. Department of Urology Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders. 400014, Chongqing, China; Chongqing Key Laboratory of Structural Birth Defect and Reconstruction. 400014, Chongqing, China; Children Urogenital Development and Tissue Engineering of Chongqing Education Commission of China, Chongqing, 400014, China. Electronic address: [email protected].
  • 5. Department of Urology Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders. 400014, Chongqing, China; Chongqing Key Laboratory of Structural Birth Defect and Reconstruction. 400014, Chongqing, China; Children Urogenital Development and Tissue Engineering of Chongqing Education Commission of China, Chongqing, 400014, China. Electronic address: [email protected].
  • 6. Department of Urology Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders. 400014, Chongqing, China; Chongqing Key Laboratory of Structural Birth Defect and Reconstruction. 400014, Chongqing, China; Children Urogenital Development and Tissue Engineering of Chongqing Education Commission of China, Chongqing, 400014, China. Electronic address: [email protected].
  • 7. Department of Urology Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders. 400014, Chongqing, China; Chongqing Key Laboratory of Structural Birth Defect and Reconstruction. 400014, Chongqing, China; Children Urogenital Development and Tissue Engineering of Chongqing Education Commission of China, Chongqing, 400014, China. Electronic address: [email protected].
  • 8. Department of Urology Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders. 400014, Chongqing, China; Chongqing Key Laboratory of Structural Birth Defect and Reconstruction. 400014, Chongqing, China; Children Urogenital Development and Tissue Engineering of Chongqing Education Commission of China, Chongqing, 400014, China. Electronic address: [email protected].
  • 9. Department of Urology Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders. 400014, Chongqing, China; Chongqing Key Laboratory of Structural Birth Defect and Reconstruction. 400014, Chongqing, China; Children Urogenital Development and Tissue Engineering of Chongqing Education Commission of China, Chongqing, 400014, China. Electronic address: [email protected].
  • 10. Department of Urology Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders. 400014, Chongqing, China; Chongqing Key Laboratory of Structural Birth Defect and Reconstruction. 400014, Chongqing, China; Children Urogenital Development and Tissue Engineering of Chongqing Education Commission of China, Chongqing, 400014, China. Electronic address: [email protected].
  • 11. Department of Urology Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders. 400014, Chongqing, China; Chongqing Key Laboratory of Structural Birth Defect and Reconstruction. 400014, Chongqing, China; Children Urogenital Development and Tissue Engineering of Chongqing Education Commission of China, Chongqing, 400014, China. Electronic address: [email protected].
  • 12. Department of Urology Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders. 400014, Chongqing, China; Chongqing Key Laboratory of Structural Birth Defect and Reconstruction. 400014, Chongqing, China; Children Urogenital Development and Tissue Engineering of Chongqing Education Commission of China, Chongqing, 400014, China. Electronic address: [email protected].
  • 13. Department of Urology Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders. 400014, Chongqing, China; Chongqing Key Laboratory of Structural Birth Defect and Reconstruction. 400014, Chongqing, China; Children Urogenital Development and Tissue Engineering of Chongqing Education Commission of China, Chongqing, 400014, China. Electronic address: [email protected].
PMID: 42264199 DOI: 10.1016/j.freeradbiomed.2026.06.015
Abstract

Triclosan (TCS) is a widely used broad-spectrum antimicrobial agent that has been demonstrated to induce damage to the male reproductive system. However, the specific mechanisms of testicular injury induced by TCS are not fully understood. In the present study, mice were treated with 0, 20 mg/kg and 40 mg/kg per day TCS from PND 56 to PND 84. Decreased sperm counts, increased sperm deformity rates, downregulation of Phosphoenolpyruvate carboxykinase (PEPCK) and Cuproptosis activation were observed. In vitro, TM4 cells were exposed to 0, 5 nM and 10 nM TCS for 24 h, which induced oxidative stress damage, inhibition of PEPCK and Cuproptosis activation. Furthermore, inhibition of PEPCK and Cuproptosis activation was rescued by Reactive Oxygen Species (ROS) scavengers N-Acetylcysteine (NAC). Besides, Cuproptosis activation induced by TCS were rescued after overexpression of PEPCK. Drug prediction with Connectivity Map (cMap) identified flubendazole and cucurbitacin-i as potential therapeutic drug. In conclusion, this study demonstrated that TCS triggered Cuproptosis activation in TM4 cells mediated by ROS storm induced PEPCK inhibition. This research also shed new insight into precise treatment of TCS-related testicular injury.

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