NF-κB is a critical transcription factor regulating immune-mediated inflammation throughout the body. In the resting state, NF-κB is inactive and sequestered in the cytoplasm by IκB proteins. Activation occurs through proteasomal degradation of IκB, allowing NF-κB to translocate to the nucleus and upregulate proinflammatory genes. Stimuli such as proinflammatory cytokines and chemokines trigger NF-κB activation, leading to cell-specific inflammatory responses. Microglia, as the primary immune responders in the central nervous system (CNS), exhibit increased NF-κB activation under pathological conditions, which can induce cell death and worsen disease pathology. NF-κB signaling includes canonical and noncanonical pathways, with the canonical pathway being central to inflammatory responses. The canonical pathway is rapidly activated by inflammatory stimuli, while the noncanonical pathway is slower and associated with adaptive immune responses. NF-κB subunits, including p65, c-Rel, RelB, p50, and p52, form dimers that regulate gene expression. In the CNS, NF-κB plays diverse roles in neurons, oligodendrocytes, astrocytes, and microglia. In neurons, NF-κB can be neuroprotective or neurodegenerative, depending on the context. In oligodendrocytes, NF-κB may have protective or dispensable roles, while in astrocytes, it is often associated with increased inflammation. Microglia, under NF-κB activation, can adopt pro-inflammatory phenotypes, contributing to neuroinflammation and disease progression. In diseases such as Alzheimer's, ALS, and hypoxic-ischemic encephalopathy, NF-κB activation in microglia is linked to neuroinflammation and neuronal damage. In Alzheimer's, NF-κB activation in microglia promotes amyloid plaque and tau tangle formation. In ALS, microglial NF-κB activation contributes to motor neuron death. In hypoxic-ischemic encephalopathy, NF-κB activation in microglia exacerbates brain injury. Targeting NF-κB in microglia may offer therapeutic potential for neurodegenerative and inflammatory CNS diseases. Further research is needed to fully understand the complex roles of NF-κB in the CNS and to develop effective interventions.NF-κB is a critical transcription factor regulating immune-mediated inflammation throughout the body. In the resting state, NF-κB is inactive and sequestered in the cytoplasm by IκB proteins. Activation occurs through proteasomal degradation of IκB, allowing NF-κB to translocate to the nucleus and upregulate proinflammatory genes. Stimuli such as proinflammatory cytokines and chemokines trigger NF-κB activation, leading to cell-specific inflammatory responses. Microglia, as the primary immune responders in the central nervous system (CNS), exhibit increased NF-κB activation under pathological conditions, which can induce cell death and worsen disease pathology. NF-κB signaling includes canonical and noncanonical pathways, with the canonical pathway being central to inflammatory responses. The canonical pathway is rapidly activated by inflammatory stimuli, while the noncanonical pathway is slower and associated with adaptive immune responses. NF-κB subunits, including p65, c-Rel, RelB, p50, and p52, form dimers that regulate gene expression. In the CNS, NF-κB plays diverse roles in neurons, oligodendrocytes, astrocytes, and microglia. In neurons, NF-κB can be neuroprotective or neurodegenerative, depending on the context. In oligodendrocytes, NF-κB may have protective or dispensable roles, while in astrocytes, it is often associated with increased inflammation. Microglia, under NF-κB activation, can adopt pro-inflammatory phenotypes, contributing to neuroinflammation and disease progression. In diseases such as Alzheimer's, ALS, and hypoxic-ischemic encephalopathy, NF-κB activation in microglia is linked to neuroinflammation and neuronal damage. In Alzheimer's, NF-κB activation in microglia promotes amyloid plaque and tau tangle formation. In ALS, microglial NF-κB activation contributes to motor neuron death. In hypoxic-ischemic encephalopathy, NF-κB activation in microglia exacerbates brain injury. Targeting NF-κB in microglia may offer therapeutic potential for neurodegenerative and inflammatory CNS diseases. Further research is needed to fully understand the complex roles of NF-κB in the CNS and to develop effective interventions.