Entrectinib attenuates LPS-induced neuroinflammation by inhibiting JNK, p38, and AKT pathways and ameliorates cognitive impairment.

Entrectinib, a Food and Drug Administration-approved medication for cancers such as non-small cell lung cancer, inhibits tropomyosin receptor kinases and penetrates the blood-brain barrier. Despite its approval, the effects of Entrectinib on neuroinflammatory responses and cognitive function within the central nervous system remain unclear. This study demonstrates that Entrectinib modulates lipopolysaccharide (LPS)-induced pro- and anti-inflammatory factors by suppressing JNK, p38, and AKT signaling, as well as NF-κB and STAT3 activity, in primary microglia. Entrectinib reduced CD16/32 levels, increased CD206 expression, enhanced phagocytic activity, and upregulated receptors and cytoskeletal genes in vitro. Additionally, Entrectinib decreased proinflammatory cytokines and inhibited JNK/p38/AKT and NF-κB/STAT3 signaling in the hippocampus of LPS-treated mice. Notably, Entrectinib ameliorated LPS-induced memory impairments in vivo. Collectively, these findings indicate that Entrectinib attenuates neuroinflammation and improves memory performance, supporting its potential therapeutic relevance for neuroinflammation-associated cognitive disorders.