Convergent Node, Divergent Failure: GPX4-SLC7A11-GSH Ferroptosis as a Unifying, Tissue-Decoded Axis of Diabetic...

Diabetic complications of the kidney, heart, retina, bone, β-cells, nervous system, vasculature, and reproductive organs have been studied as separate diseases. Iron-dependent phospholipid peroxidation may be a unifying upstream vulnerability rather than the dominant death morphology; we organized the evidence into five levels. Metabolic ignition (L1) loads the substrate via glucolipotoxic polyunsaturated-fatty-acid/ACSL4 priming and ferritinophagic iron release. These pressures act on the central defense network (L2): glutathione peroxidase 4 (GPX4), SLC7A11/xCT, and glutathione (GSH). Gain-of-function restoration attenuates diabetic injury, and loss-of-function evidence is correlative. We do not call this GPX4-dependent network rate-limiting; graded manipulation of endogenous GPX4 has not been performed in diabetic tissues. Glutathione-independent arms act in parallel but differ in status, GCH1-BH4 appears depleted, FSP1 uncharacterized, and DHODH unestablished and contested. Diabetes disables this node through transcriptional, post-translational, epigenetic, non-coding-RNA, and organelle-specific routes (L3) rather than one lesion. Each tissue decodes the same failure into a distinct organ program (L4) set by its architecture and functional demands, and shared regulators may act oppositely across compartments. Extracellular-vesicle and gut-organ axes couple these programs (L5a), but the insulin-resistance relationship is directionally unresolved: AMPK-NRF2-GPX4 evidence is limited and pharmacological, and glutathione peroxidase loss can itself improve insulin sensitivity. Translation (L5b) returns the same target: reduced GPX4 and SLC7A11 with elevated ACSL4 recurs across complications and is associated with severity. Evidence is predominantly preclinical, and human data are almost entirely observational. The framework is hypothesis-generating rather than clinically actionable, and the null-to-unfavorable record of global antioxidant and NRF2-directed trials indicates that interventions must be cell- and context-resolved.