Inhibition of ferroptosis counteracts the advanced maternal age-induced oocyte deterioration

Ferroptosis, a recently discovered form of programmed cell death triggered by the excessive accumulation of iron-dependent lipid peroxidation products, plays a critical role in the development of various diseases. However, whether it is involved in the age-related decline in oocyte quality remains unexplored. Here, we took advantage of nano-proteomics to uncover that reduced ferritin heavy chain (Fth1) level is a major cause leading to the occurrence of ferroptosis in aged oocytes. Specifically, induction of ferroptosis in young oocytes by its activators RSL3 and FAC, or knockdown of Fth1 all phenocopied the meiotic defects observed in aged oocytes, including failed oocyte meiotic maturation, aberrant cytoskeleton dynamics, as well as impaired mitochondrial function. Transcriptome analysis showed that knockdown of Fth1 affected meiosis-related and aging-related pathways in oocytes. Conversely, inhibition of ferroptosis by its inhibitors or expression of Fth1 improved the quality of aged oocytes. We also validated the effects of ferroptosis on the porcine oocyte quality in vitro. Altogether, we demonstrate the contribution of ferroptosis to the age-induced oocyte defects and evidence that inhibition of ferroptosis might be a feasible strategy to ameliorate the reproductive outcomes of female animals at an advanced age.