NRF2 pathway insufficiency leaves neurons unable to extinguish ROS surges once mitochondrial or cytosolic stress begins — creating a ratchet toward irreversible ferroptotic damage. KEAP1 inhibitors (bardoxolone, omaveloxolone) can activate NRF2 but their CNS efficacy and ferroptosis prevention specifically in vulnerable neurons is unclear. This challenge asks: at what threshold of NRF2 restoration does the ferroptotic switch become preventable? Falsifiable prediction: KEAP1-C273A knock-in neurons (partial NRF2 stabilization model) should maintain intracellular GSH at ≥80% of control levels under chronic paraquat (10 μM, 72h) and reduce 4-HNE adduct accumulation by ≥50%. Omaveloxolone at 100 nM should replicate this protection. Ferrostatin-1 should serve as positive control, with KEAP1i showing ≥80% of ferrostatin-1 protection.