Microglial SIRT6 confers protection against neuroinflammation-associated depression through NRF2-HO1 signaling.

Microglia-mediated neuroinflammation is widely recognized as a key contributor to various neurological diseases and psychiatric disorders, including depression; however, its underlying mechanisms remain incompletely understood. In this study, we observed a significant reduction in SIRT6 expression in neural cells, alongside a marked increase in microglial SIRT6, in a lipopolysaccharide (LPS)-induced depression model. We demonstrated that microglia-specific Sirt6 knockout (Sirt6MCKO) mice exhibited clear morphological signs of microglial activation, elevated levels of inflammatory cytokines, and enhanced peroxidative damage, ultimately leading to aggravated depression-like behaviors. Mechanistically, SIRT6 was found to regulate microglial activation via the NRF2-HO1 signaling pathway in this model. This regulatory role was substantiated by the observation that microglia-specific Nrf2 knockout mice phenocopied the depressive-like phenotypes of Sirt6MCKO mice under LPS challenge. Conversely, overexpression of Nrf2 in Sirt6MCKO mice markedly attenuated microglial activation, peroxidative damage, and depressive behaviors. Notably, specific reintroduction of SIRT6 in microglia fully rescued the pathological phenotypes in Sirt6MCKO mice. In a translational approach, pharmacological activation of SIRT6 with UBCS039 robustly suppressed microglial activation, along with its downstream inflammatory and peroxidative effects, thereby ameliorating depression-like behaviors and nominating UBCS039 as a novel therapeutic candidate for depression.