Premature ovarian failure (POF) is a prevalent and lethal adverse event that severely affects female cancer patients receiving chemotherapy. It is highly correlated with the collateral damage to ovarian granulosa cells caused by ferroptosis. The excessive iron accumulation in the intracellular labile iron pool (LIP) and the aberrant generation of reactive oxygen species (ROS) is the major cause of ferroptosis. No compounds with both ferroptosis inhibition functions and ovarian-targeting specificity that do not reduce systemic chemotherapeutic efficacy have been successful in treating the POF in the clinic trials. We herein in report a multifunctional FSH-mPDA@DFO nanoparticle that can prevent chemotherapy-induced DFO by targeting LIP and ROS to restrict ferroptosis. The FSH-mPDA@DFO are constructed by encapsulating deferoxamine (DFO) within mesoporous polydopamine nanoparticles conjugated with an ovarian granulosa cell-targeting peptide (FSHβ). They downregulate transferrin receptor (TFRC) expression, reduce cellular iron ion uptake, and inhibit ferritinophagy-mediated iron mobilization, thereby ameliorating LIP overload and regulating iron metabolism. More importantly, FSH-mPDA@DFO nanoparticles can specifically accumulate in the mitochondria and suppress excessive mitophagy to preserve mitochondrial integrity and attenuate iron release and ROS generation. In vivo experiments demonstrate that FSH-mPDA@DFO nanoparticles improve oocyte quantity and quality while restoring fertility and endocrine homeostasis in chemotherapy-induced POF mice. Collectively, FSH-mPDA@DFO nanoparticles hold a great potential for clinical prevention and treatment of POF patients.

ROCK1, one of the Rho GTPases, plays an important role in primordial follicle reserve and follicular development. ROCK1 was primarily expressed in the cytoplasm of oocytes and granulosa cell in mice. Inhibition of ROCK1 significantly reduced the primordial follicle reserve and delayed growing follicle development. ROCK1 regulates primordial follicular reserve and follicle development through the HIPPO signaling pathway. These findings shed new lights on the physiology of sustaining female reproduction.

In female mammals, the size of the initially established primordial follicle pool within the ovaries determines the reproductive life span. Interestingly, the establishment of the primordial follicle pool is accompanied by a remarkable programmed oocyte loss for unclear reasons. Here, we identify a new role of ASH1-like histone lysine methyltransferase (ASH1L) in controlling the apoptosis of oocytes during meiotic prophase I in mice. Our results showed that overexpression of Ash1l led to a dramatic loss of fetal oocytes via apoptosis, which subsequently resulted in a reduced capacity of the primordial follicle pool. Overexpression of Ash1l also led to a deficiency in DNA double-strand break repair associated with premature upregulation of p63 and phosphorylated checkpoint kinase 2 (p-CHK2), the major genome guardian of the female germline, following Ash1l overexpression in fetal ovaries. In summary, ASH1L is one of the indispensable epigenetic molecules that acts as a guardian of the genome. It protects oocyte genome integrity and removes oocytes with serious DNA damage by regulating the expression of p63 and p-CHK2 during meiotic prophase I in mice. Our study provides a perspective on the physiological regulatory role of DNA damage checkpoint signaling in fetal oocyte guardianship and female fertility.

In this study, our results show that p300 expression increases with primordial follicle activation. A p300 inhibitor results in premature activation of primordial follicles in cultured mouse ovaries. Conversely, the ratio of primordial follicle activation markedly decreases upon culturing with the p300 agonist. Furthermore, p300 regulates primordial follicle activation by inhibiting Vegfa transcription in granulosa cells.