NRF2-TERT-ACSL4 pathway inhibits ferroptosis and regulates cytoskeletal dynamics to mitigate ovarian aging

Ovarian aging is a major contributor to female reproductive decline and is associated with oxidative stress, ferroptosis, and cytoskeletal disorganization. However, the molecular mechanisms regulating ferroptosis during ovarian aging and the therapeutic strategies to mitigate it remain insufficiently understood. Here, we investigated the role of the NRF2/TERT/ACSL4 signaling axis in ferroptosis regulation and cytoskeletal remodeling during ovarian aging and explored the therapeutic potential of a moderate static magnetic field (SMF, 100 mT) as a non-pharmacological intervention to activate NRF2 signaling. Using naturally aged female mice and D-galactose (D-gal)-induced senescent granulosa-like KGN cells, combined with histological, biochemical, mitochondrial, and molecular analyses, as well as pharmacological validation using NRF2 modulation (including ML385 and SFN), and telomerase inhibition (BIBR1532) to elucidate the underlying mechanisms. We found that SMF markedly attenuated ovarian senescence and D-gal-induced senescence by activating the NRF2/TERT/ACSL4 axis, thereby maintaining intracellular iron homeostasis, inhibiting ferroptotic injury, and restoring F-actin cytoskeletal organization. Mechanistically, NRF2 directly bound to and transcriptionally upregulated TERT expression, and the Glu79 residue was required for NRF2-dependent regulation of TERT. Further analyses showed that phosphorylated p62 at Ser349 competitively interacted with the Arg483 site of KEAP1, facilitating NRF2 dissociation and activation, while SMF exposure functioned as an external trigger that facilitated these molecular events. In conclusion, activation of the NRF2/TERT/ACSL4 signaling axis constitutes a central protective mechanism against ovarian aging by coordinating ferroptosis suppression and cytoskeletal remodeling. Targeting this pathway-through biophysical interventions such as static magnetic field exposure-may help preserve ovarian function during aging.