Senolytics通过消除衰老细胞来缓解环磷酰胺诱导的卵巢早衰

摘要(中文译文)

烷化剂，尤其是环磷酰胺（CY），以其高毒性而著称，可导致年轻癌症幸存者出现医源性早发性卵巢功能不全（POI）和不孕。目前，有效的预防和治疗策略仍然有限。鉴于化疗可诱导细胞衰老，我们研究了达沙替尼（D）和槲皮素（Q）的治疗潜力，这是一种已知可清除衰老细胞的衰老细胞清除药物组合。利用CY诱导的小鼠卵巢损伤模型，我们发现CY处理增加了卵巢中衰老细胞的积累。由此产生的衰老相关分泌表型（SASP）导致卵巢微环境恶化，表现为卵泡闭锁增加和卵泡数量下降，最终导致POI。我们的研究结果表明，DQ疗法通过清除衰老细胞和减少SASP分泌，有效减轻了CY诱导的损伤。在临床层面，DQ给药恢复了性激素水平和动情周期的规律性，使各发育阶段的卵泡数量总体增加。此外，DQ治疗显著改善了动情周期的规律性，使60%的CY+DQ小鼠恢复了规律周期，而单独CY组仅为约15%（p<0.0001）。RNA测序分析显示，DQ治疗上调了Pagr1a——一个与胚外发育相关的基因，同时下调了参与衰老诱导的基因（Itgb3、Wnt10b、Vegfa）和免疫功能相关基因（A2m、Ccl21d）。这些结果表明，衰老细胞驱动了CY诱导的卵巢损伤，而DQ代表了一种有前景的治疗策略，可用于保护女性癌症患者的卵巢储备和内分泌功能。

Abstract

Alkylating agents, particularly cyclophosphamide (CY), are known for their high toxicity, which can lead to iatrogenic premature ovarian insufficiency (POI) and infertility in young cancer survivors. Currently, effective prevention and treatment strategies remain limited. Given that chemotherapy induces cellular senescence, we investigated the therapeutic potential of dasatinib (D) and quercetin (Q), a senolytic combination known to eliminate senescent cells. Using a CY-induced murine model of ovarian injury, we found that CY treatment increased the accumulation of senescent cells in the ovaries. The resulting senescence-associated secretory phenotype (SASP) led to a deterioration of the ovarian microenvironment, characterized by increased follicular atresia and a decline in follicle quantity, ultimately culminating in POI. Our findings demonstrate that DQ therapy effectively mitigated CY-induced damage by clearing senescent cells and reducing SASP secretion. Clinically, DQ administration restored sex hormone levels and regularity of the estrous cycle, resulting in an overall increase in follicle numbers across all developmental stages. Furthermore, DQ treatment significantly normalized estrous cyclicity, restoring regular cycles in 60% of the CY+DQ mice compared to only ~15% in the CY-alone group (p<0.0001). RNA sequencing analysis revealed that DQ treatment upregulated Pagr1a, a gene associated with extraembryonic development, while downregulating genes involved in senescence induction (Itgb3, Wnt10b, Vegfa) and immune function (A2m, Ccl21d). These results suggest that senescent cells drive CY-induced ovarian damage and that DQ represents a promising therapeutic strategy for preserving the ovarian reserve and endocrine function in female cancer patients.

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