Transferrin restrains rather than drives neuronal ferroptosis after intracerebral haemorrhage

Introduction The transferrin‐transferrin receptor axis is the principal route by which neurons acquire iron, and it is generally regarded as a driver of ferroptosis: transferrin receptor 1 is used as a ferroptosis marker, and blocking transferrin‐bound iron uptake is protective in several models of iron‐dependent injury. That framework predicts that transferrin should be harmful after intracerebral haemorrhage (ICH), a condition defined by catastrophic iron overload. Clinical observations point the other way, since patients with higher circulating transferrin have smaller haematomas and better outcomes Methods We resolved this contradiction using bidirectional, neuron‐targeted manipulation of transferrin in a rat autologous‐blood model of ICH. Transferrin was silenced or overexpressed in neurons with adeno‐associated virus given 3 weeks beforehand, the same manipulations were applied to hemin-exposed differentiated PC‐12 neurons, transcriptomes were sequenced, and recombinant apo‐transferrin was given intraperitoneally 1 h after ICH at 4, 10 or 20 mg/kg. Results Endogenous transferrin increased two‐ to threefold in perihaematomal neurons and microglia, peaking on day 3, the same time point at which ferroptotic injury was maximal. Silencing neuronal transferrin did not protect; it increased perihaematomal iron, hydrogen peroxide, and malondialdehyde; shrank neuronal mitochondria further; and enlarged the lesion. Overexpression produced the mirror image, driving iron below sham levels and halving neurodegeneration. Inversion was reproduced in hemin‐exposed PC‐12 neurons. Transcriptionally, transferrin did not reinforce antioxidant defence. It abolished the need for it. Hemin moved 6,976 genes in wild‐type neurons but only 343 in transferrin‐overexpressing ones, a 95% collapse of the injury programme. Across the 6,974 hemin‐responsive genes, the effect of transferrin ran opposite to the effect of hemin (Pearson r = −0.869), reversing 99% of the genes that both perturbations moved significantly. The hemin‐induced oxidative stress programme, including the HO‐1/SLC7A11/TXNRD1 module, returned towards baseline. Recombinant apo‐transferrin given 1 h after ICH reproduced these effects with a sharp threshold at 20 mg/kg, halved lesion volume, and restored sensorimotor and cognitive function at 14 days. Discussion We propose that ICH inverts transferrin's function: confronted with heme‐derived iron that bypasses the transferrin cycle, transferrin is repurposed from an iron donor towards a high‐affinity extracellular iron sink. Its buffering capacity, rather than iron load itself, sets the threshold for neuronal ferroptosis. That capacity is exhaustible, saturating well below what the injured brain requires.