L-DOPA influences transferrin-dependent iron release at the blood-brain barrier

Iron dysregulation in the brain is a pathological hallmark of Parkinson’s disease (PD) and contributes to oxidative stress and neurodegeneration. How the blood-brain barrier (BBB), the principal regulator of brain iron homeostasis, is implicated in this process particularly in the context of dopaminergic therapies remains unclear. In the brain interstitial space, apo-transferrin (apo-Tf), signals iron deficiency and promotes endothelial iron release, whereas holo-transferrin (holo-Tf) signals iron sufficiency and suppresses export. Here, we investigated how dopaminergic drugs modulate this transferrin-dependent regulatory system using human iPSC-derived brain endothelial cells. We quantified 55Fe release, intracellular iron retention, and expression of key iron-regulatory proteins. Our findings showed that L-DOPA acts as a potent driver of iron release, significantly increasing 55Fe efflux within just 1 h and sustaining it through 24 h. Importantly, apo- and holo-Tf preserved their opposing regulatory roles, however, the overall magnitude of iron export was increased under both conditions. These results demonstrated that L-DOPA acts by altering the normal parenchymal fine-tuning of endothelial iron release. Additionally, L-DOPA treatment reduced expression of the iron export protein ferroportin (FPN1) but intracellular 55Fe levels decreased, suggesting that FPN1 downregulation reflects a compensatory response to iron depletion rather than a limitation on export. Holo-Tf selectively downregulated transferrin receptor 1 (TfR1) and ferritin light chain (FTL), consistent with feedback inhibition of iron import and storage under iron-sufficient signaling. Selegiline, by contrast, produced delayed and modest effects and preserved transporter and ferritin expression across both apo- and holo-Tf conditions. These findings identify a previously unrecognized direct interaction between dopaminergic therapy and parenchymal transferrin signaling, positioning L-DOPA as a significant modulator of BBB iron export and revealing a mechanism through which PD treatments may negatively influence regional brain iron balance.