Oxidoreductase delivery by cell therapies in cyclophosphamide-induced premature ovarian insufficiency: a mechanistic insight into ovarian rejuvenation.

BACKGROUND: The etiologically diverse decline in ovarian function among females represents a significant contributor to the rising incidence of infertility. Recent advances in cell-based therapies, including mesenchymal stem cells (MSCs) and autologous stromal vascular fraction (SVF), has shown potential in rejuvenating ovarian function. Yet, the efficacy heterogeneity and mechanisms of action warrant further investigation for validation. METHODS: This study investigates the therapeutic efficacy of human umbilical cord-derived MSCs (HucMSCs), adipose tissue-derived MSCs (ADSCs), and stromal vascular fraction (SVF) in a cyclophosphamide (CTX)-induced premature ovarian insufficiency (POI) mouse model. Equivalent doses of these cells were orthotopically administered, and their impact on ovarian function was meticulously evaluated using comprehensive functional and histological assays. RNA sequencing and proteomic analysis were employed to elucidate the underlying mechanisms. RESULTS: Our findings reveal that HucMSCs, ADSCs, and SVF robustly enhance follicle development, hormonal balance, oocyte quality, and embryonic developmental potential, leading to improved fertility outcomes. In vitro co-culture with granulosa cells (GCs) demonstrated that all three cell types significantly promoted GC proliferation. Proteomic evaluation identified oxidoreductase enzymes as key players in mitigating ovarian injury by alleviating oxidative stress within oocytes and GCs. CONCLUSIONS: These results underscore the therapeutic potential of HucMSCs, ADSCs, and SVF in rejuvenating ovarian function and highlight their promise as versatile and effective cell-based therapies for clinical application in female infertility. This study provides critical insights and a foundation for advancing the clinical translation of these cell-based materials as promising agents for female infertility, offering new hope for women facing ovarian dysfunction. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13048-025-01912-y.