(2R,6R)-HNK improved LPS-induced depression-like behavior by inhibiting Vcam1/Caspase-1/IL-1β pathway.
International immunopharmacology August 1, 2026 Jinghua Zhao, Ruxin Zhang, Jiarui Pan et al.
The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) reduces depression-like behavior in mice by suppressing neuroinflammation and neuronal pyroptosis. In experiments with male C57BL/6J mice and PC12 cells, HNK lowered expression of NLRP3, caspase-1, GSDMD, and interleukin-1β at both protein and mRNA levels, lessened neuronal injury, and reduced lactate dehydrogenase release. Transcriptomic analysis identified Vcam1 as a key differentially expressed gene. Overexpressing Vcam1 increased pyroptosis markers, while HNK reduced Vcam1 expression; knocking down Vcam1 had opposite effects. HNK thus attenuates LPS-induced pyroptosis and neuroinflammation partly by downregulating the Vcam1/caspase-1/IL-1β pathway, offering insights for depression treatment.