Knockdown of USP22 alleviates LPS-induced microglial inflammation and mouse depressive-like behaviors via KAT2A

Neuropsychopharmacology. 2025 Aug 20. doi: 10.1038/s41386-025-02207-y. Online ahead of print.

ABSTRACT

Depression is a chronic mental illness that has emerged as the second most prevalent disease globally, characterized by symptoms such as low mood, reduced interest, and cognitive impairment. The onset of depression has been associated with microglial inflammation, but the molecular mechanisms behind this are not well understood. Here, we investigated the mechanisms involved in the roles of microglial inflammation in promoting depression by establishing a mouse model of inflammation-related depression via lipopolysaccharide (LPS) administration. We found that LPS treatment led to microglial activation and increased the deubiquitinating enzyme, USP22, expression in the mouse hippocampus. Further, knockdown of USP22 in microglia inhibited depressive-like behaviors and intracerebral inflammation in the mouse model. Moreover, subsequent mechanistic analyses revealed that KAT2A, which serves as a ubiquitination substrate, is modulated by USP22, thereby influencing mitochondrial damage and oxidative stress in microglia. Our findings indicate that USP22 facilitates oxidative stress and inflammatory responses in microglia through the deubiquitination of KAT2A, providing a promising target for the development of therapeutic strategy for the depression treatment.

PMID:40836042 | DOI:10.1038/s41386-025-02207-y