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We previously showed that reducing neuronal pyruvate kinase M2 (PKM2) aggravates oxidative damage and accelerates dopaminergic neuron loss, although the mechanism remained unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In the MPTP mouse model, we evaluated antioxidant responses and neuronal survival after selectively deleting PKM2 in dopaminergic neurons or overexpressing PKM2. In MPP\n                      <jats:sup>+<\/jats:sup>\n                      \u2010treated 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Neuronal PKM2 knockdown abolished MPTP\u2010induced 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\n                      <jats:sup>+<\/jats:sup>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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\u2013Nrf2 axis thus emerges as a candidate target for disease\u2010modifying therapy in PD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cns.70968","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T05:21:31Z","timestamp":1780377691000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Upregulated\n                    <scp>PKM2<\/scp>\n                    Protects Dopaminergic Neurons From Oxidative Damage Through Nrf2 Transactivation in an\n                    <scp>MPTP<\/scp>\n                    \u2010Induced Mouse Model of Parkinson's Disease"],"prefix":"10.1002","volume":"32","author":[{"given":"Meng","family":"Mei","sequence":"first","affiliation":[{"name":"Department of Pharmacy Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology  Wuhan China"},{"name":"School of 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