• Melatonin mitigates ovarian aging in murine models by significantly decreasing m6A methylation levels.
• YTHDF2 expression is markedly increased in ovarian granulosa cells upon melatonin treatment, with differentially methylated genes enriched in the polyubiquitination pathway.
• YTHDF2 enhances UBE3C expression by modulating m6A methylation of UBE3C mRNA, reducing P53 senescence factor and alleviating ovarian aging.
• This study reveals a novel epigenetic mechanism (YTHDF2/m6A/UBE3C axis) underlying melatonin's anti-aging effects on the ovary, offering potential therapeutic targets for infertility.