Mei Liping, Chen Le, Zhang Bingfei, Jia Xianbo, Gan Xiang, Sun Wenqiang
Key Laboratory of Livestock and Poultry Multi-Omics, Ministry of Agriculture and Rural Affairs, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu 611130, China.
Scientific Research Center, Guilin Medical University, Guilin 541199, China.
Int J Mol Sci. 2025 Jun 24;26(13):6045. doi: 10.3390/ijms26136045.
Granulosa cells (GCs) are essential for follicular growth and development, and their functional state critically impacts folliculogenesis. , a transcriptionally active isoform of the gene, is crucial for maintaining follicular integrity. In this study, we demonstrate that overexpression promotes ferroptosis in bovine GCs by downregulating , depleting intracellular glutathione (GSH), and enhancing lipid peroxidation, particularly under Erastin treatment. By contrast, knockdown restores antioxidant capacity, elevates GSH levels, and attenuates ferroptosis. To elucidate the underlying mechanism, untargeted metabolomic profiling revealed that overexpression significantly altered the metabolic landscape of GCs, with marked enrichment in the glutathione metabolism pathway. Notably, betaine-a metabolite closely linked to redox homeostasis-was markedly downregulated. Functional assays confirmed that exogenous betaine supplementation restored expression, increased GSH levels, and alleviated oxidative damage induced by either HO or overexpression. Moreover, betaine co-treatment effectively reversed lipid peroxide accumulation and mitigated -induced ferroptosis. Collectively, our findings identify a novel mechanism by which promotes ferroptosis in granulosa cells through the suppression of betaine and glutathione metabolism, highlighting betaine as a key metabolic modulator with promising protective potential.
颗粒细胞（GCs）对卵泡的生长和发育至关重要，其功能状态对卵泡发生有着关键影响。 基因的一种转录活性异构体 对维持卵泡完整性至关重要。在本研究中，我们证明 过表达通过下调 、消耗细胞内谷胱甘肽（GSH）以及增强脂质过氧化作用，特别是在埃拉斯汀处理下，促进牛颗粒细胞中的铁死亡。相比之下， 敲低可恢复抗氧化能力、提高GSH水平并减轻铁死亡。为了阐明潜在机制，非靶向代谢组学分析显示 过表达显著改变了颗粒细胞的代谢格局，谷胱甘肽代谢途径显著富集。值得注意的是，与氧化还原稳态密切相关的代谢物甜菜碱显著下调。功能试验证实，外源性补充甜菜碱可恢复 表达、提高GSH水平并减轻由HO或 过表达诱导的氧化损伤。此外，甜菜碱联合处理有效地逆转了脂质过氧化物的积累并减轻了 诱导的铁死亡。总体而言，我们的研究结果确定了一种新机制，即 通过抑制甜菜碱和谷胱甘肽代谢促进颗粒细胞中的铁死亡，突出了甜菜碱作为一种具有潜在保护潜力的关键代谢调节剂。
