Cadmium, a heavy metal, disrupts cellular homeostasis and is highly toxic, with no effective treatments currently available against its toxicity. According to studies, phytochemicals provide a promising strategy for mitigating cadmium toxicity. Naringenin (NG), a potent antioxidant found primarily in citrus fruits, showed protective properties against cadmium toxicity in rats. Nonetheless, the precise mechanism of cadmium cytotoxicity in fibroblasts remains unknown. This study evaluated NG against cadmium (CdCl2) toxicity utilizing network pharmacology and in silico molecular docking, and was further validated experimentally in rat fibroblast F111 cells. Using network pharmacology, 25 possible targets, including the top 10 targets of NG against cadmium, were identified. Molecular docking of interleukin 6 (IL6), the top potential target with NG, showed robust binding with an inhibition constant (Ki) of 58.76 μM, supporting its potential therapeutic potential. Pathway enrichment analysis suggested that “response to reactive oxygen species” and “negative regulation of small molecules metabolic process” were the topmost pathways targeted by NG against cadmium. In vitro analysis showed that NG (10 μM) attenuated CdCl2‐induced oxidative stress by reducing altered intracellular ROS, mitochondrial mass, and membrane potential. Also, NG reversed CdCl2‐mediated nuclear damage, G2/M phase arrest, and apoptosis. GC/MS‐based metabolomics of F111 cells revealed CdCl2 reduced cholesterol levels, which led to alterations in primary bile acid, steroid and steroid hormone biosynthesis pathways, whereas, NG restored these alterations. In summary, combined in silico and in vitro analysis suggested that NG protected cells from CdCl2 toxicity by mitigating oxidative stress and metabolic pathway alterations, providing a comprehensive understanding of its protective mechanisms against cadmium‐induced toxicity.

中文翻译：

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柚皮素对成纤维细胞镉毒性的抵抗：一种综合网络药理学和体外代谢组学方法


镉是一种重金属，会破坏细胞稳态并且具有剧毒，目前没有针对其毒性的有效治疗方法。根据研究，植物化学物质为减轻镉毒性提供了一种很有前途的策略。柚皮素 （NG） 是一种主要存在于柑橘类水果中的强效抗氧化剂，对大鼠表现出对镉毒性的保护特性。尽管如此，成纤维细胞中镉细胞毒性的确切机制仍然未知。本研究利用网络药理学和计算机分子对接评估了 NG 对镉 （CdCl2） 毒性的影响，并在大鼠成纤维细胞 F111 细胞中进一步实验验证。使用网络药理学，确定了 25 个可能的靶点，包括 NG 针对镉的前 10 个靶点。白细胞介素 6 （IL6） 是 NG 的首要潜在靶标，其分子对接显示出强大的结合，抑制常数 （Ki） 为 58.76 μM，支持其潜在的治疗潜力。通路富集分析表明，“对活性氧的反应”和“小分子代谢过程的负调节”是 NG 针对镉的最主要途径。体外分析表明，NG （10 μM） 通过减少改变的细胞内 ROS、线粒体质量和膜电位来减轻 CdCl2 诱导的氧化应激。此外，NG 逆转了 CdCl2 介导的核损伤、G2/M 期停滞和细胞凋亡。基于 GC/MS 的 F111 细胞代谢组学显示 CdCl2 降低了胆固醇水平，这导致原代胆汁酸、类固醇和类固醇激素生物合成途径的改变，而 NG 恢复了这些改变。 总之，计算机和体外分析相结合表明，NG 通过减轻氧化应激和代谢途径改变来保护细胞免受 CdCl2 毒性，从而全面了解其对镉诱导毒性的保护机制。