Upregulated PKM2 Protects Dopaminergic Neurons From Oxidative Damage Through Nrf2 Transactivation in an MPTP ‐Induced Mouse Model of Parkinson's Disease

Background The death of dopaminergic neurons in the substantia nigra pars compacta (SNc) is the core defining pathological change of Parkinson's disease (PD). We previously showed that reducing neuronal pyruvate kinase M2 (PKM2) aggravates oxidative damage and accelerates dopaminergic neuron loss, although the mechanism remained unclear. Methods In the MPTP mouse model, we evaluated antioxidant responses and neuronal survival after selectively deleting PKM2 in dopaminergic neurons or overexpressing PKM2. In MPP + ‐treated primary neurons, we examined how ROS influences hnRNP A1/A2 and alternative splicing toward PKM2, and we tested reversibility by knocking down hnRNP A1/A2 or scavenging ROS. Results Neuronal PKM2 knockdown abolished MPTP‐induced activation of Nrf2 target genes, exacerbated lipid peroxidation and DNA damage, and accelerated loss of dopaminergic neurons, whereas PKM2 overexpression restored the antioxidant response and mitigated neurodegeneration. Mechanistically, ROS generated by MPP + increased hnRNP A1/A2, promoting alternative splicing toward PKM2 and elevating its abundance; conversely, hnRNP A1/A2 knockdown or ROS scavenging reversed this splicing shift and attenuated the antioxidant response. Conclusion These findings delineate a signaling pathway in which ROS elevate hnRNP A1/A2, favor PKM2 production, and activate Nrf2, thereby providing a mechanistic basis for the oxidative injury and progressive dopaminergic neuron degeneration observed with PKM2 loss. The PKM2–Nrf2 axis thus emerges as a candidate target for disease‐modifying therapy in PD.