Targeting p75NTR activity alleviates the neurotoxic effect of high glucose on iPSC-derived dopaminergic neurons

• High glucose induces DNA damage, JNK activation, and cell death in human iPSC-derived dopaminergic neurons. • The pro-NGF/p75NTR axis is upregulated under hyperglycemic conditions and mediates glucose neurotoxicity; p75NTR inhibition rescues neuronal death. • Glucose overload sensitizes dopaminergic neurons to 6-OHDA toxicity, which is reversed by p75NTR blockade. • High glucose-treated glial cells acquire an inflammatory phenotype and release neurotoxic factors, contributing to neurodegeneration.