DNA damage, cGAS–STING signaling, ferroptosis, and senescence in therapy-induced ovarian injury: emerging molecular targets for fertility preservation

Cancer therapies have substantially improved survival among girls and women with cancer, but chemotherapy and radiotherapy can impair ovarian endocrine function and fertility by damaging the finite follicular reserve and its supporting microenvironment. This mini-review compares the initiating lesions and cellular targets of chemotherapy and ionizing radiation and examines how they converge on DNA damage response (DDR), apoptosis, senescence, inflammation, and regulated cell death. Alkylating agents, platinum compounds, and anthracyclines differ in the DNA lesions, mitochondrial stress, and follicular compartments they affect, whereas radiation combines direct and indirect DNA damage with vascular, stromal, and fibrotic injury. We evaluate evidence linking cytosolic DNA sensing by cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS–STING) to sterile inflammation and senescence and distinguish experimentally supported ferroptosis from nonspecific oxidative stress. Evidence for these emerging pathways ranges from direct gonadotoxicity models to ovarian aging, reproductive toxicology, and ovarian cancer models, and is therefore graded according to biological context. We also discuss reversibility, recovery of ovarian function, and antioxidant, anti-ferroptotic, anti-inflammatory, and ovarian niche-protective strategies. Since cancer control remains the first therapeutic priority, ovarian protectants require simultaneous demonstration of reproductive benefit and preserved antitumor efficacy.