Decreased FTO Expression Promotes Ovarian Granulosa Cells Aging.

This study aimed to investigate the role of fat mass and obesity-associated protein (FTO), an N6-methyladenosine (m⁶A) demethylase, in ovarian aging by examining the effects of FTO downregulation on key biological processes in human ovarian granulosa cells (KGN), including proliferation, apoptosis regulation, senescence, and steroidogenic function. Stable FTO knockdown in KGN cells was achieved using lentivirus, complemented by modeling premature senescence with H₂O₂ treatment. The biological functions, such as cell proliferation, apoptosis, aging, and sex hormone secretion, were assessed using RT-qPCR, WB, EdU staining, and ELISA, respectively. Silencing FTO significantly inhibited the proliferation of KGN cells, promoted apoptosis and senescence, and disrupted their endocrine function. These effects were consistent in the H₂O₂-induced senescence model. Our findings identify FTO as a critical regulator of ovarian homeostasis. Depletion of FTO impairs granulosa cell viability, accelerates senescence-related functional decline, and diminishes steroidogenic capacity through m⁶A-mediated modulation of key biosynthetic enzymes. These insights highlight FTO as a potential therapeutic target for age-related ovarian dysfunction.