Tabasi Rahele, Ghasemian Fatemeh, Tavana Somayeh
Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran.
Department of Biology, Faculty of Sciences, University of Guilan, Rasht, Iran.
Life Sci. 2025 Aug 1;374:123697. doi: 10.1016/j.lfs.2025.123697. Epub 2025 May 8.
This review investigates the regulatory functions of sphingolipids-particularly sphingosine-1-phosphate (S1P) and ceramide-in the process of ovarian folliculogenesis. It emphasizes how the dynamic balance between ceramide and S1P, orchestrated by enzymes like sphingomyelinase, ceramidase, and sphingosine kinase (SphK1/2), governs follicle development, survival, and reproductive potential.
A comprehensive review of recent experimental and clinical studies was performed to examine the impact of sphingolipids and their metabolic enzymes on follicular activation, growth, and maturation. Special focus was placed on the signaling mechanisms mediated by S1P and ceramide in ovarian cells.
Sphingolipids are essential mediators of proliferation, differentiation, and programmed cell death during folliculogenesis. S1P enhances follicle survival and growth by activating S1P receptors (notably S1PR1 and S1PR3), which in turn stimulate PI3K/Akt/mTOR and ERK/MAPK signaling cascades. Additionally, S1P-induced calcium mobilization via Gq- and Gi-coupled pathways supports metabolic resilience and cellular longevity. Acting as a pro-survival factor, S1P is particularly influential during physiological events such as the LH surge. Conversely, ceramide-whether derived from sphingomyelin hydrolysis or de novo synthesis-accumulates in mitochondria and promotes apoptosis by activating Bax and suppressing Bcl-2 family proteins. The interplay between ceramide and S1P, often referred to as the "sphingolipid rheostat," plays a central role in determining follicular destiny.
Modulating sphingolipid signaling and its enzymatic regulators holds promise as a therapeutic avenue for enhancing ovarian function and treating gynecological conditions. This review highlights the critical importance of maintaining a functional ceramide/S1P balance to preserve follicular viability and overall reproductive health.
本综述研究了鞘脂类，特别是1-磷酸鞘氨醇（S1P）和神经酰胺，在卵巢卵泡发生过程中的调节功能。着重阐述了由鞘磷脂酶、神经酰胺酶和鞘氨醇激酶（SphK1/2）等酶所调控的神经酰胺和S1P之间的动态平衡，是如何支配卵泡发育、存活及生殖潜能的。
对近期的实验和临床研究进行全面综述，以考察鞘脂类及其代谢酶对卵泡激活、生长和成熟的影响。特别关注S1P和神经酰胺在卵巢细胞中介导的信号传导机制。
鞘脂类是卵泡发生过程中增殖、分化和程序性细胞死亡的重要介质。S1P通过激活S1P受体（特别是S1PR1和S1PR3）来提高卵泡的存活率和生长速度，进而刺激PI3K/Akt/mTOR和ERK/MAPK信号级联反应。此外，S1P通过Gq和Gi偶联途径诱导钙动员，支持代谢恢复力和细胞寿命。作为一种促生存因子，S1P在诸如促黄体生成素高峰等生理事件中具有特别重要的影响。相反，无论是源自鞘磷脂水解还是从头合成的神经酰胺，都会在线粒体中积累，并通过激活Bax和抑制Bcl-2家族蛋白来促进细胞凋亡。神经酰胺和S1P之间的相互作用，通常被称为“鞘脂类变阻器”，在决定卵泡命运方面起着核心作用。
调节鞘脂类信号传导及其酶调节剂有望成为增强卵巢功能和治疗妇科疾病的治疗途径。本综述强调了维持功能性神经酰胺/S1P平衡对于保持卵泡活力和整体生殖健康的至关重要性。
