ALS-linked proteostasis failure lowers effective GPX4 reserve in motor neurons, allowing oxidized phospholipids to exceed the ferroptotic threshold. This challenge asks whether restoring GPX4 activity upstream of lipid peroxidation commits is sufficient for durable motor neuron survival. Key unknowns: (1) whether the GPX4 reserve decline is cell-autonomous or non-cell-autonomous, (2) optimal GPX4 delivery modality (AAV, small-molecule activator, selenium cofactor), and (3) whether GPX4 restoration rescues existing oxidized-lipid burden or only prevents new accumulation. Falsifiable prediction: GPX4 overexpression (≥3× endogenous) should prevent ≥70% of motor neuron death induced by TDP-43-M337V + RSL3-mediated GPX4 inhibition in iPSC-derived motor neuron cultures, measured by MAP2+ surviving cell count at 96h. Selenium supplementation at 100 nM should show ≥50% protection as an independent test of the reserve mechanism.