Melatonin alleviates ferroptosis triggered by cadmium via regulating ferritinophagy and iron metabolism in spermatogonia

褪黑素通过调节精原细胞中的铁蛋白自噬和铁代谢来减轻镉引起的铁死亡

Authors：Didi Jia, Wei Huang, Qizi Yin, Han Wang, Ziyue Wang, Mingming Zhang, Wenjing Gong, Rong Wang, Yan Zhu, Yanli Ji

Source：Scientific Reports

DOI: 10.1038/s41598-025-93822-8

Abstract

Melatonin (Mel), a classical antioxidant, has the potential to mediate ferroptosis. Cadmium (Cd) poses a substantial threat to the male reproductive system, as it can induce testicular injury by triggering ferroptosis. The study aimed to explore the protective role and mechanism of Mel in Cd-induced ferroptosis in spermatogonia (spg). Our results demonstrated that Cd disrupted the mitochondrial ultrastructure and induced more autophagosomes in spg. Exposure to Cd resulted in a reduction of the mitochondrial membrane potential of the cells. The transcriptomics analysis revealed significant differences in gene expression associated with ferroptosis and autophagy. Mel could reverse the changes caused by Cd in the genes mentioned above. Furthermore, Cd increased cellular iron content and elevated reactive oxygen species levels, which induced oxidative stress in spg. Mel pretreatment reduced iron accumulation and oxidative damage caused by Cd exposure. Additional studies demonstrated that Cd exposure activated NCOA4-mediated ferritinophagy in spg. Mel pretreatment, as anticipated, inhibited the increased the mRNA and protein expression of ATG5, LC3B, and NCOA4 caused by Cd, ameliorated Cd-caused iron overload and oxidative stress, and protected spg from ferroptosis. Our study provides a therapeutic basis for the use of Mel to treat Cd-induced testicular injury.

Keywords: Cadmium; Ferritinophagy; Ferroptosis; Melatonin; Spermatogonia.

摘要：

褪黑素（Mel）是一种经典的抗氧化剂，具有调控铁死亡的潜力。镉（Cd）对男性生殖系统造成严重威胁，可通过诱发铁死亡导致睾丸损伤。本研究旨在探讨Mel对镉诱导精原细胞（spg）铁死亡的保护作用及机制。结果表明，镉会破坏精原细胞线粒体超微结构并诱发更多自噬体形成，同时导致细胞线粒体膜电位降低。转录组学分析显示，铁死亡和自噬相关基因表达存在显著差异，而Mel能逆转镉对上述基因的影响。此外，镉会提高细胞铁含量和活性氧水平，引发精原细胞氧化应激；Mel预处理能减少镉暴露导致的铁蓄积和氧化损伤。进一步研究发现，镉暴露会激活精原细胞中NCOA4介导的铁蛋白自噬。Mel预处理可抑制镉诱导的ATG5、LC3B和NCOA4 mRNA及蛋白表达上调，改善镉引发的铁过载和氧化应激，从而保护精原细胞免于铁死亡。本研究为应用褪黑素治疗镉诱导的睾丸损伤提供了理论依据。

关键词：镉；噬铁蛋白；铁突变；褪黑激素；精原细胞