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 ( Sirt6 MCKO) 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 Sirt6 MCKO mice under LPS challenge. Conversely, overexpression of Nrf2 in Sirt6 MCKO 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. • SIRT6 shows opposing expression patterns in LPS-induced depression: decreased in neurons but markedly increased in microglia. • Microglia-specific Sirt6 knockout exacerbates neuroinflammation, oxidative damage, and depression-like behaviors. • SIRT6 in microglia regulates activation and neuroinflammation through the NRF2-HO1 signaling pathway. • Microglial NRF2 deficiency mimics, while its overexpression rescues, the depressive phenotypes of Sirt6 knockout mice. • Pharmacological SIRT6 activation by UBCS039 inhibits microglial activation and alleviates depression-like behaviors, suggesting a novel therapeutic strategy.