Steroid Biosynthesis Pathway Counteracts Iron Overload-Induced Ferroptosis in Mouse Granulosa Cells

Area of Science:

• Reproductive biology
• Cellular and molecular mechanisms of infertility
• Iron metabolism and oxidative stress

Background:

• Iron overload is a known cause of female reproductive dysfunction.
• The precise cellular mechanisms linking iron overload to infertility are not fully understood.
• Ovarian granulosa cells are crucial for female fertility and are potential targets of iron toxicity.

Purpose of the Study:

• To investigate the impact of iron overload on ovarian granulosa cells.
• To identify the molecular pathways involved in iron overload-induced female infertility.
• To explore the protective role of steroid biosynthesis against ferroptosis in granulosa cells.

Main Methods:

• Established a mouse model of ovarian iron overload using ferric citrate.
• Performed metabolomic and transcriptomic analyses on granulosa cells.
• Utilized cell culture experiments with iron treatment, gene knockdown, and iron chelation.

Main Results:

• Iron overload disrupted estrous cycles, reduced estradiol, impaired follicle development, and decreased fertility in mice.
• Granulosa cells showed ferroptosis markers, reduced antioxidants, and lipid peroxidation.
• Steroid biosynthesis genes (Hmgcr, Fdft1) and SREBF2 were upregulated; SREBF2 activation protected against ferroptosis.

Conclusions:

• Iron overload induces ferroptosis in granulosa cells, leading to female infertility.
• The steroid biosynthesis pathway, regulated by SREBF2, acts as an endogenous anti-ferroptotic mechanism.
• Targeting the steroid biosynthesis pathway may offer a therapeutic strategy for iron overload-induced infertility.