MASLD does not affect fertility and senolytics fail to prevent MASLD progression in male mice.

ABSTRACT

Senescent cells have been linked to the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the effectiveness of senolytic drugs in reducing liver damage in mice with MASLD is not clear. Additionally, MASLD has been reported to adversely affect male reproductive function. Therefore, this study aimed to evaluate the protective effect of senolytic drugs on liver damage and fertility in male mice with MASLD. Three-month-old male mice were fed a standard diet (SD) or a choline-deficient western diet (WD) until 9 months of age. At 6 months of age mice were randomized within dietary treatment groups into senolytic (dasatinib + quercetin [D + Q]; fisetin [FIS]) or vehicle control treatment groups. We found that mice fed choline-deficient WD had liver damage characteristic of MASLD, with increased liver size, triglycerides accumulation, fibrosis, along increased liver cellular senescence and liver and systemic inflammation. Senolytics were not able to reduce liver damage, senescence and systemic inflammation, suggesting limited efficacy in controlling WD-induced liver damage. Sperm quality and fertility remained unchanged in mice developing MASLD or receiving senolytics. Our data suggest that liver damage and senescence in mice developing MASLD is not reversible by the use of senolytics. Additionally, neither MASLD nor senolytics affected fertility in male mice.