Targeting NEK7 modulates pyroptosis and gut microbiota to alleviate depression-like behavior in rats

NIMA-associated kinase 7 (NEK7) is a serine/threonine kinase that regulates the aberrant activation of the inflammasome of NOD-like receptor thermal protein domain associated protein 3 (NLRP3), which leads to inflammatory diseases. Depression, a prevalent psychiatric condition, has been linked to neuroinflammatory processes. However, the precise molecular and cellular mechanisms underlying the role of NEK7 in depression pathogenesis remain incompletely characterized. Our study demonstrated elevated NEK7 expression in the hippocampus of maternal separation (MS) and chronic unpredictable mild stress (CUMS)-induced depressed rats. Adeno-associated virus (AAV)-mediated delivery of shNEK7 effectively alleviated depression-like behavioral deficits, downregulated pyroptosis marker protein expression, reduced inflammatory cytokine levels (interleukin-1β and interleukin-18), and preserved neuronal survival and cellular structure. Furthermore, hippocampal NEK7 knockdown restored gut microbiota homeostasis in depression-like rats, particularly affecting the relative abundance of Corynebacterium and Prevotella genera. Notably, for the first time, the metabolite corynoxine was found to be associated with hippocampal NEK7 knockdown in depression-like rats. Taken together, our results reveal that NEK7 may be a promising target for the treatment of depression and provide new experimental evidence for clinical application.