Mechanistically, PHGDH-mediated serine synthesis protected oligodendrocytes from oxidative stress-induced death by promoting glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH) production through the one-carbon metabolism pathway.<h4>Conclusion</h4>This study reveals the role of PHGDH-mediated <i>de novo</i> serine synthesis in reducing oligodendrocyte death which may provide a potential target for improving neurological function after ischemic stroke. The gene discussed is PHGDH; the disease is ischemic stroke.