Overall, our results demonstrated for the first time that hippocampal neuron necroptosis activates microglia through the TLR4/MyD88 signaling pathway in PTX-induced cognitive impairment, promoting M1 polarization and neuroinflammation, while inhibiting necroptosis promotes M2 polarization and neuroprotection. The gene discussed is MYD88; the disease is Cognitive impairment.