Cyclophosphamide induces ovarian granulosa cell ferroptosis via a mechanism associated with HO-1 and ROS-mediated...

Area of Science:

• Reproductive Biology
• Cellular Biology
• Toxicology

Background:

• Granulosa cell (GC) death is implicated in cyclophosphamide (CTX)-induced primary ovarian insufficiency (POI).
• Understanding the mechanisms of GC death is crucial for developing therapeutic strategies for POI.

Purpose of the Study:

• To investigate the role of ferroptosis in CTX-induced GC death and its contribution to POI.
• To explore the potential of targeting heme oxygenase 1 (HO-1) as a therapeutic intervention.

Main Methods:

• RNA sequencing and bioinformatics analysis of CTX-exposed GCs.
• Cell culture experiments using COV434 and KGN cells treated with CTX.
• Assessment of iron levels, reactive oxygen species (ROS), lipid peroxidation, mitochondrial function, and membrane potential.
• Evaluation of HO-1 inhibition effects on ferroptosis.

Main Results:

• CTX exposure induced ferroptosis in GCs, characterized by upregulated HO-1 and downregulated glutathione peroxidase-4 (GPX4).
• Iron overload and disrupted ROS homeostasis (cytoROS, mtROS, lipROS) were observed in CTX-treated GCs, linked to HO-1 upregulation and mitochondrial dysfunction.
• HO-1 inhibition effectively suppressed CTX-induced ferroptosis and GPX4 depletion.

Conclusions:

• Ferroptosis, driven by HO-1 upregulation and mitochondrial dysfunction, plays a significant role in CTX-induced GC death and POI.
• HO-1 modulators show promise in mitigating CTX-induced ovarian damage, offering a potential therapeutic avenue for POI patients.