2. Academic Validation
  3. Cadmium exposure induces Leydig cell injury via necroptosis caused by oxidative stress and TNF-α/TNFR1 signaling

Cadmium exposure induces Leydig cell injury via necroptosis caused by oxidative stress and TNF-α/TNFR1 signaling

  • Biochem Biophys Res Commun. 2025 May 1:761:151717. doi: 10.1016/j.bbrc.2025.151717.
Xiaoping Zheng 1,  Yaohui Sun 2,  Jinhua Wang 3,  Yinghao Yin 3,  Zitaiyu Li 3,  Biao Liu 3,  Hongji Hu 3,  Jiarong Xu 3,  Yingbo Dai 4,  Yashpal S Kanwar 5,  Yuxin Tang 6
Affiliations

Affiliations

  • 1 Department of Urology, The Fifth Affiliated Hospital of Sun Yat-sen University, No.52 Meihua Dong Road, ZhuHai, 519000, China; Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China; Department of Pathology & Medicine, FSM, Northwestern University, Chicago, IL, USA.
  • 2 Department of Thoracic Surgery and Lung Transplantation, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, 519000, Guangdong, China.
  • 3 Department of Urology, The Fifth Affiliated Hospital of Sun Yat-sen University, No.52 Meihua Dong Road, ZhuHai, 519000, China; Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China.
  • 4 Department of Urology, The Fifth Affiliated Hospital of Sun Yat-sen University, No.52 Meihua Dong Road, ZhuHai, 519000, China; Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China. Electronic address: [email protected].
  • 5 Department of Pathology & Medicine, FSM, Northwestern University, Chicago, IL, USA. Electronic address: [email protected].
  • 6 Department of Urology, The Fifth Affiliated Hospital of Sun Yat-sen University, No.52 Meihua Dong Road, ZhuHai, 519000, China; Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, 519000, China. Electronic address: [email protected].
PMID: 40188597 DOI: 10.1016/j.bbrc.2025.151717
Abstract

Cadmium, a ubiquitous environmental pollutant, has been linked to testicular damage, primarily through mechanisms such as oxidative stress and various forms of programmed cell death. Despite extensive studies on its toxic effects, the specific role of Necroptosis in cadmium-induced reproductive toxicity remains unclear. In this study, we provide critical insights into how cadmium triggers Necroptosis in Leydig cells, leading to testicular dysfunction. Using both in vitro and in vivo models, we demonstrated that cadmium exposure induces necroptotic cell death in Leydig cells, with significant involvement of the TNF-α/TNFR1 signaling pathway and Reactive Oxygen Species (ROS) generation. Co-treatment with Nec-1, a specific Necroptosis inhibitor, significantly reduced elevated ROS levels and suppressed TNF-α/TNFR1-induced necroptotic cell death, suggesting that ROS and the TNF-α/TNFR1 signaling pathway contribute to Necroptosis activation in cadmium-induced Leydig cell injury. In conclusion, we demonstrate that Necroptosis is a key driver of cadmium-induced testicular damage, suggesting that targeting Necroptosis could offer novel therapeutic strategies for mitigating reproductive toxicity caused by heavy metals.

Keywords

Cadmium; Leydig cell; Necroptosis; Reactive oxygen species (ROS); TNF- α.

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