Abstract

Background:Premature ovarian failure (POF) refers to the loss of ovarian function in women younger than 40 years of age. Its incidence has increased annually, with a progressively younger age at onset. Women of reproductive age undergoing cancer treatments, such as radiotherapy and chemotherapy, may experience ovarian damage, leading to POF. Cyclophosphamide (CTX), a widely used chemotherapeutic agent, is a major cause of POF and severely compromises the reproductive health of female cancer survivors. However, the mechanism underlying CTX-induced ovarian damage remains not fully elucidated, and effective therapeutic strategies are lacking. Methods:Oxidative stress and cholesterol metabolism in ovarian tissues and cells following CTX treatment were assessed using enzyme-linked immunosorbent assay (ELISA), qRT-PCR, and Western blotting (WB). In vitro experiments were performed using mouse primary ovarian theca cells and granulosa cells to evaluate the impacts of CTX on oxidative stress and cholesterol metabolism, with the antioxidant lycopene (Lyc) administered as an interventional treatment. Additionally, in vivo therapeutic studies using Lyc were conducted to evaluate its regulatory effects on oxidative stress and cholesterol metabolism. Results:CTX triggers oxidative stress by enhancing reactive oxygen species (ROS) production and suppressing ROS clearance. CTX-induced ROS accumulation impairs cholesterol uptake and metabolic pathways. Specifically, CTX significantly downregulates the protein expression of low-density lipoprotein receptor (LDLR) and steroidogenic acute regulatory protein (StAR) in ovarian tissues and primary ovarian theca cells, leading to impairments in cholesterol transport and metabolism. Findings from both in vitro and in vivo assays showed that Lyc intervention markedly attenuates CTX-induced ROS accumulation, restores the expression of antioxidant enzymes and associated genes, and enhances the protein levels of LDLR a