The melatonin-FTO-ATF4 signaling pathway protects granulosa cells from cisplatin-induced chemotherapeutic toxicity by suppressing ferroptosis.

IF 3.2 3区医学 Q2 GENETICS & HEREDITY Journal of Assisted Reproduction and Genetics Pub Date : 2024-10-10 DOI:10.1007/s10815-024-03276-6

Rongli Wang, Jing Geng

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Abstract

Purpose: In cisplatin-induced premature ovarian failure (POF) mice, granulosa cells showed a high level of ferroptosis. Previous research has indicated that the fat mass and obesity-associated protein/activating transcription factor 4 (FTO/ATF4) axis was involved in the regulation of ferroptosis. The purpose of this study was to explore the role of the FTO/ATF4 axis in cisplatin-induced ferroptosis in granulosa cell.

Methods: The extent of ferroptosis was assessed by transmission electron microscopy (TEM) and ROS, GPX, GSH, and MDA assays. Western blotting was used to evaluate the protein expression levels of ferroptosis-related molecules. Ferroptosis activator and inhibitor were also used.

Results: We found that ferroptosis increased in a concentration-dependent manner in cisplatin-induced injured granulosa cells, accompanied by the downregulation of FTO. In addition, gain- and loss-of-function studies showed that FTO affects ferroptosis in injured cells by regulating ATF4 expression. Ferrostatin-1 inhibited the effect of FTO downregulation on injured granulosa cells ferroptosis, and erastin reversed the protective effect of FTO on ferroptosis in injured granulosa cells. Finally, melatonin was used, and we found that melatonin reduced ferroptosis in cisplatin-induced injured granulosa cells by upregulating FTO expression.

Conclusion: Our study demonstrated that cisplatin induced granulosa cell ferroptosis by downregulating the expression of FTO. ATF4 was identified as a downstream target of FTO, and overexpression of ATF4 reversed the effects of decreased FTO on ferroptosis. Additionally, melatonin mitigates the cytotoxic effects of cisplatin by upregulating FTO expression. The melatonin-FTO-ATF4 signaling pathway plays a vital role in the treatment of cisplatin-induced POF.

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褪黑激素-FTO-ATF4信号通路通过抑制铁突变保护颗粒细胞免受顺铂诱导的化疗毒性的影响。

目的：在顺铂诱导的卵巢早衰（POF）小鼠中，颗粒细胞显示出高水平的铁凋亡。先前的研究表明，脂肪量和肥胖相关蛋白/激活转录因子 4（FTO/ATF4）轴参与了铁突变的调控。本研究的目的是探讨FTO/ATF4轴在顺铂诱导的颗粒细胞铁沉降中的作用：方法：通过透射电子显微镜（TEM）和 ROS、GPX、GSH 及 MDA 检测评估铁变态反应的程度。用 Western 印迹法评估铁突变相关分子的蛋白表达水平。还使用了铁突变激活剂和抑制剂：结果：我们发现在顺铂诱导的损伤颗粒细胞中，铁突变以浓度依赖的方式增加，同时伴随着 FTO 的下调。此外，功能增益和功能缺失研究表明，FTO通过调节ATF4的表达影响损伤细胞的铁凋亡。铁前列素-1抑制了FTO下调对损伤颗粒细胞铁凋亡的影响，而麦拉宁则逆转了FTO对损伤颗粒细胞铁凋亡的保护作用。最后，使用褪黑素，我们发现褪黑素通过上调FTO的表达减少了顺铂诱导的损伤颗粒细胞的铁梭形细胞增多：结论：我们的研究表明，顺铂通过下调 FTO 的表达诱导颗粒细胞铁沉降。ATF4被确定为FTO的下游靶标，过表达ATF4可逆转FTO表达减少对铁凋亡的影响。此外，褪黑激素通过上调 FTO 的表达减轻了顺铂的细胞毒性作用。褪黑激素-FTO-ATF4信号通路在治疗顺铂诱导的POF中发挥了重要作用。

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来源期刊

Journal of Assisted Reproduction and Genetics 医学-妇产科学

CiteScore

5.70

自引率

9.70%

发文量

286

审稿时长

1 months

期刊介绍： The Journal of Assisted Reproduction and Genetics publishes cellular, molecular, genetic, and epigenetic discoveries advancing our understanding of the biology and underlying mechanisms from gametogenesis to offspring health. Special emphasis is placed on the practice and evolution of assisted reproduction technologies (ARTs) with reference to the diagnosis and management of diseases affecting fertility. Our goal is to educate our readership in the translation of basic and clinical discoveries made from human or relevant animal models to the safe and efficacious practice of human ARTs. The scientific rigor and ethical standards embraced by the JARG editorial team ensures a broad international base of expertise guiding the marriage of contemporary clinical research paradigms with basic science discovery. JARG publishes original papers, minireviews, case reports, and opinion pieces often combined into special topic issues that will educate clinicians and scientists with interests in the mechanisms of human development that bear on the treatment of infertility and emerging innovations in human ARTs. The guiding principles of male and female reproductive health impacting pre- and post-conceptional viability and developmental potential are emphasized within the purview of human reproductive health in current and future generations of our species. The journal is published in cooperation with the American Society for Reproductive Medicine, an organization of more than 8,000 physicians, researchers, nurses, technicians and other professionals dedicated to advancing knowledge and expertise in reproductive biology.