The female ovary contains a finite number of oocytes, and their release at ovulation becomes sporadic and disordered with aging and with obesity, leading to loss of fertility. Understanding the molecular defects underpinning this pathology is essential as age of childbearing and obesity rates increase globally. We identify that fibrosis within the ovarian stromal compartment is an underlying mechanism responsible for impaired oocyte release, which is initiated by mitochondrial dysfunction leading to diminished bioenergetics, oxidative damage, inflammation, and collagen deposition. Furthermore, antifibrosis drugs (pirfenidone and BGP-15) eliminate fibrotic collagen and restore ovulation in reproductively old and obese mice, in association with dampened M2 macrophage polarization and up-regulated MMP13 protease. This is the first evidence that ovarian fibrosis is reversible and indicates that drugs targeting mitochondrial metabolism may be a viable therapeutic strategy for women with metabolic disorders or advancing age to maintain ovarian function and extend fertility.

中文翻译：

---

通过从小鼠卵巢中靶向去除纤维化胶原蛋白来延长雌性生殖寿命

女性卵巢含有有限数量的卵母细胞，随着年龄的增长和肥胖，它们在排卵时的释放变得零星和紊乱，导致生育能力下降。随着全球生育年龄和肥胖率的增加，了解支撑这种病理学的分子缺陷至关重要。我们发现卵巢间质腔内的纤维化是导致卵母细胞释放受损的潜在机制，这是由线粒体功能障碍引发的，导致生物能量减少、氧化损伤、炎症和胶原沉积。此外，与抑制 M2 巨噬细胞极化和上调 MMP13 蛋白酶有关的抗纤维化药物（吡非尼酮和 BGP-15）消除了生殖衰老和肥胖小鼠的纤维化胶原蛋白并恢复排卵。