Reduced fertility induced by MASLD in female mice is improved by senolytic treatment†

Senescent cells have been implicated in the pathogenesis of metabolic dysfunction-associated liver disease (MASLD), which can negatively affect female fertility. Senolytic drugs are reported to eliminate senescent cells in various tissues, including the ovary. However, the efficacy of senolytic drugs in reducing liver damage and preserving fertility in female mice with MASLD remains unclear. Therefore, this study aimed to evaluate the protective effect of senolytic drugs on liver damage and fertility in reproductive-aged female mice with MASLD. Three-month-old female mice were fed a standard diet (SD) or Western diet (WD) to induce MASLD until 9 months of age. Starting at 6 months of age, mice were also randomized to receive senolytic treatment (dasatinib + quercetin, D + Q) or vehicle within each diet. We observed that mice fed the WD exhibited liver damage characteristic of MASLD, with increased liver size, triglyceride accumulation, and fibrosis. These mice also exhibited increased liver senescence and inflammation. Senolytic treatment slightly reduced liver mass and modulated some liver senescence and inflammation-related genes, suggesting limited efficacy in controlling WD-induced liver damage. Pregnancy rates were reduced in mice with MASLD and improved by senolytic treatment. Mice with MASLD had increased ovarian senescence, inflammation, and fibrosis, which was attenuated by senolytic treatment, despite having no effect on the ovarian follicle reserve. We conclude that senolytic treatment has potential for improving reproductive function in aged female mice with MASLD, despite limited impact in liver and systemic indicators.